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Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future
Open accessAbstract
Amyloid β protein (Aβ) is the main component of neuritic plaques in Alzheimer’s disease (AD), and its accumulation has been considered as the molecular driver of Alzheimer’s pathogenesis and progression. Aβ has been the prime target for the development of AD therapy. However, the repeated failures of Aβ-targeted clinical trials have cast considerable doubt on the amyloid cascade hypothesis and whether the development of Alzheimer’s drug has followed the correct course. However, the recent successes of Aβ targeted trials have assuaged those doubts. In this review, we discussed the evolution of the amyloid cascade hypothesis over the last 30 years and summarized its application in Alzheimer’s diagnosis and modification. In particular, we extensively discussed the pitfalls, promises and important unanswered questions regarding the current anti-Aβ therapy, as well as strategies for further study and development of more feasible Aβ-targeted approaches in the optimization of AD prevention and treatment.
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TL;DR
This review argues that Aβ accumulation remains a central driver of AD and that recent anti-Aβ successes—including FDA approval of aducanumab and lecanemab—have revived the amyloid cascade hypothesis. It summarizes Aβ biology, biomarkers, and anti-Aβ drug development while outlining persistent challenges such as insufficient specificity, inadequate animal models, late treatment, and loss of physiological Aβ functions.
Key findings
- Of 298 AD therapies in clinical trials (ALZFORUM, March 2023), 76 target Aβ or its aggregates; 38 were discontinued due to ineffectiveness or toxic side effects, and two antibody-based drugs—aducanumab and lecanemab—have been approved by the FDA.
- Lecanemab’s Phase 3 trial reduced cognitive and functional decline as measured by CDR-SB by 27% versus placebo; ARIA occurred in around 21% of lecanemab-treated individuals versus just over 9% of placebo controls. Donanemab’s partial Phase 3 results showed a 35% slowing of cognitive and functional decline, with 47% of treated participants showing no clinical progression at 1 year versus 29% on placebo.
- BACE1 inhibitors and γ-secretase inhibitors/modulators largely failed or were discontinued because of toxicity, lack of substrate specificity, or insufficient efficacy; examples include LY2886721, atabecestat, elenbecestat, lanabecestat, umibecestat, avagacestat, and several γ-secretase modulators.
- Soluble Aβ at physiological levels has reported functions including enhancement of LTP, stimulation of neuronal differentiation, promotion of injury recovery, antimicrobial activity, tumor suppression, antioxidant effects, neurogenesis, and maintenance of BBB integrity, so therapies should ideally target fibrils, protofibrils, or oligomers while preserving normal Aβ monomers.
Methods
- Narrative review; no systematic review protocol, search strategy, or formal evidence appraisal is stated.
- Sources include published literature and clinical trial registries, specifically ALZFORUM (March 2023) and clinicaltrials.gov (accessed March 19, 2023), plus cited references.
- Main analysis is a narrative synthesis of the amyloid cascade hypothesis, Aβ aggregation and pathological roles, Aβ-based biomarkers, anti-Aβ therapies, challenges, and future directions.
Limitations
- The paper states that anti-Aβ therapy faces disturbed physiological functions of soluble Aβ, insufficient specificity (e.g., γ-secretase and BACE1 off-target effects), lack of accurate animal models, and late application relative to biomarker onset.
- It states that current animal models mainly mimic familial AD and cannot fully reflect late-onset sporadic AD complexity, including aging, human immune differences, and extensive neuronal loss.
- Evident from the text: as a narrative review, it does not describe systematic search or selection criteria, quality appraisal, or quantitative synthesis; conclusions rely on author interpretation of the cited literature.
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Claims the paper makes
205 Not checked yet · 21 Own interpretation · 9 No basis given · 1 Supported · 1 Own result
Every source the paper cites for this claim was checked and supports it.
In the paper
“A change in CSF Aβ levels can be detected even up to 25 years before a patient begins to show symptoms.478”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Late application
What the sources say
- Supportedcites [478] McDade, E. et al. Longitudinal cognitive and biomarker changes in dominantly inherited Alzheimer disease. Neurology 91, e1295–e1306 (2018). source
The Results report that Aβ showed detectable change beginning at least 25 years before estimated symptom onset and identify CSF Aβ42 as one of the measures. The Discussion says CSF Aβ42 and PET amyloid began changing at nearly the same time. This timing is an estimate from people with dominantly inherited Alzheimer disease, not an observation of each patient's eventual symptom onset. (LLM, conf=0.90)
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In the paper
“There is an elevation of Aβ peptides during traumatic brain injury (TBI), indicating that Aβ may belong to the pathological cascade of TBI or be an agent for improving recovery.395,396”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [395] Chen, X. H., Johnson, V. E., Uryu, K., Trojanowski, J. Q. & Smith, D. H. A lack of amyloid beta plaques despite persistent accumulation of amyloid beta in axons of long-term survivors of traumatic brain injury. Brain Pathol. 19, 214–223 (2009). source
- Not checked yetcites [396] Pajoohesh-Ganji, A. et al. Inhibition of amyloid precursor protein secretases reduces recovery after spinal cord injury. Brain Res. 1560, 73–82 (2014). source
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In the paper
“Animal models with the expression of human Aβ showed stronger resistance to bacterial and viral infections.365”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [365] Kumar, D. K. et al. Amyloid-beta peptide protects against microbial infection in mouse and worm models of Alzheimer’s disease. Sci. Transl. Med 8, 340ra372 (2016). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Aβ40 peptides were intracerebroventricularly injected into TBI-impacted BACE1–/– mice, which significantly improved motor memory deficits in these injured mice, suggesting the protective effect of Aβ.362”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [362] Mannix, R. C., Zhang, J., Berglass, J., Qui, J. & Whalen, M. J. Beneficial effect of amyloid beta after controlled cortical impact. Brain Inj. 27, 743–748 (2013). source
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In the paper
“reduction of endogenous Aβ levels by using γ-secretase inhibitor DAPT or deleting the enzyme BACE1 attenuated the functional recovery in mice with spinal cord injury (SCI).396”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [396] Pajoohesh-Ganji, A. et al. Inhibition of amyloid precursor protein secretases reduces recovery after spinal cord injury. Brain Res. 1560, 73–82 (2014). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“overexpression of human APP (hAPP695) leads to an obvious lower infarct volume in the cortex of mice suffering from cerebral ischemia.363”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [363] Clarke, J. et al. Overexpression of APP provides neuroprotection in the absence of functional benefit following middle cerebral artery occlusion in rats. Eur. J. Neurosci. 26, 1845–1852 (2007). source
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In the paper
“Aβ peptides are able to interact and entrap various bacterial strains and viruses, such as HSV1 and HSV6, block their entry into the host cells to replicate.402–404”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [402] Spitzer, P. et al. Amyloidogenic amyloid-beta-peptide variants induce microbial agglutination and exert antimicrobial activity. Sci. Rep. 6, 32228 (2016). source
- Not checked yetcites [403] Eimer, W. A. et al. Alzheimer’s disease-associated beta-amyloid is rapidly seeded by herpesviridae to protect against brain infection. Neuron 99, 56–63.e53 (2018). source
- Not checked yetcites [404] Bourgade, K. et al. beta-Amyloid peptides display protective activity against the human Alzheimer’s disease-associated herpes simplex virus-1. Biogerontology 16, 85–98 (2015). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Aβ stimulated the aggregation of viral particles, which facilitated leukocyte-mediated uptake of viruses.405”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [405] White, M. R. et al. Alzheimer’s associated beta-amyloid protein inhibits influenza A virus and modulates viral interactions with phagocytes. PLoS One 9, e101364 (2014). source
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In the paper
“Aβ42 peptides enhanced the transcription of p53, which is responsible for controlling cell apoptosis.412,413”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [412] Ohyagi, Y. et al. Intracellular Abeta42 activates p53 promoter: a pathway to neurodegeneration in Alzheimer’s disease. FASEB J. 19, 255–257 (2005). source
- Not checked yetcites [413] Alves da Costa, C. et al. Presenilin-dependent gamma-secretase-mediated control of p53-associated cell death in Alzheimer’s disease. J. Neurosci. 26, 6377–6385 (2006). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Both Aβ40 and Aβ42 in physiological concentrations prevented lipoprotein oxidation in CSF and plasma.364,421”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [364] Kontush, A. et al. Amyloid-beta is an antioxidant for lipoproteins in cerebrospinal fluid and plasma. Free Radic. Biol. Med 30, 119–128 (2001). source
- Not checked yetcites [421] Zou, K., Gong, J. S., Yanagisawa, K. & Michikawa, M. A novel function of monomeric amyloid beta-protein serving as an antioxidant molecule against metal-induced oxidative damage. J. Neurosci. 22, 4833–4841 (2002). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Aβ treatment was found to effectively inhibit the production of proinflammatory T helper cells (TH1 and TH17) and the related cytokines including IL-6, IFN-γ and IL-17, which improved motor paralysis in EAE animal models.”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [397] Grant, J. L. et al. Reversal of paralysis and reduced inflammation from peripheral administration of beta-amyloid in TH1 and TH17 versions of experimental autoimmune encephalomyelitis. Sci. Transl. Med 4, 145ra105 (2012). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Aβ peptides also bound to fungal cells and stimulated the phagocytosis of microglia.408”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [408] Wu, Y. et al. Microglia and amyloid precursor protein coordinate control of transient Candida cerebritis with memory deficits. Nat. Commun. 10, 58 (2019). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Aβ42 induced oxidative stress and decreased the expression of X-linked inhibitor of apoptosis (XIAP), which directly inhibited key proteases of the apoptosis pathway including caspase 3, 7 and 9.414,415”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [414] Yamamori, H., Tanaka, T., Kudo, T. & Takeda, M. Amyloid-beta down-regulates XIAP expression in human SH-SY5Y neuroblastoma cells. Neuroreport 15, 851–854 (2004). source
- Not checked yetcites [415] Chaudhary, A. K. et al. A potential role of X-linked inhibitor of apoptosis protein in mitochondrial membrane permeabilization and its implication in cancer therapy. Drug Disco. Today 21, 38–47 (2016). source
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In the paper
“brain tissues from AD patients show higher anti-microbial activity than samples from age-matched non-AD individuals, which was correlated with Aβ levels in brain.398”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [398] Soscia, S. J. et al. The Alzheimer’s disease-associated amyloid beta-protein is an antimicrobial peptide. PLoS One 5, e9505 (2010). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Aβ40 mainly drived differentiation of NPCs into neurons, differing from Aβ42, which increased glia markers in NPCs.359”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [359] Chen, Y. & Dong, C. Abeta40 promotes neuronal cell fate in neural progenitor cells. Cell Death Differ. 16, 386–394 (2009). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“verteporfin only bound with the APP transmembrane domain rather than the transmembrane domain of the Notch-1 receptor, indicating its inhibitory effect is in a C99-specific manner.437”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Insufficient specificity
What the sources say
- Not checked yetcites [437] Castro, M. A. et al. Verteporfin is a substrate-selective gamma-secretase inhibitor that binds the amyloid precursor protein transmembrane domain. J. Biol. Chem. 298, 101792 (2022). source
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In the paper
“Aβ42 stimulated the expression of Bax, which induced cell apoptosis and was commonly observed in many cancers.416,417”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [416] Clementi, M. E. et al. Alzheimer’s amyloid beta-peptide (1–42) induces cell death in human neuroblastoma via bax/bcl-2 ratio increase: an intriguing role for methionine 35. Biochem Biophys. Res. Commun. 342, 206–213 (2006). source
- Not checked yetcites [417] Liu, Z. et al. Direct activation of Bax protein for cancer therapy. Med Res Rev. 36, 313–341 (2016). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“the damaged host cells released nucleic acids containing Aβ aggregates, which were immunogenic and elicited the secretion of type I interferons (IFNs) by adjacent microglia to accomplish the antiviral response.406”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [406] Di Domizio, J. et al. Nucleic acid-containing amyloid fibrils potently induce type I interferon and stimulate systemic autoimmunity. Proc. Natl Acad. Sci. USA 109, 14550–14555 (2012). source
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In the paper
“genetic deletion of CatB significantly increased Aβ42 burden and worsened amyloid deposition in AD mice, whereas overexpression of CatB reduced amyloid plaques.497”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > Perspective and future direction > Combination therapy and mechanism-based therapy
What the sources say
- Not checked yetcites [497] Mueller-Steiner, S. et al. Antiamyloidogenic and neuroprotective functions of cathepsin B: implications for Alzheimer’s disease. Neuron 51, 703–714 (2006). source
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In the paper
“Treatment with rapamycin significantly stimulated autophagy associated with markedly reduced both intracellular Aβ and extracellular amyloid deposition in brains as well as improved cognitive deficits in AD mice.503,504”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > Perspective and future direction > Combination therapy and mechanism-based therapy
What the sources say
- Not checked yetcites [503] Caccamo, A., Majumder, S., Richardson, A., Strong, R. & Oddo, S. Molecular interplay between mammalian target of rapamycin (mTOR), amyloid-beta, and Tau: effects on cognitive impairments. J. Biol. Chem. 285, 13107–13120 (2010). source
- Not checked yetcites [504] Majumder, S., Richardson, A., Strong, R. & Oddo, S. Inducing autophagy by rapamycin before, but not after, the formation of plaques and tangles ameliorates cognitive deficits. PLoS One 6, e25416 (2011). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“PET imaging allows us to visualize Aβ fibrils in patients, which accumulate in an Alzheimer’s brain as early as 15 years before the onset of symptoms.477”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Late application
What the sources say
- Not checked yetcites [477] Benzinger, T. L. et al. Regional variability of imaging biomarkers in autosomal dominant Alzheimer’s disease. Proc. Natl. Acad. Sci. USA 110, E4502–E4509 (2013). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Although crenezumab did not significantly improve cognitive impairment in the participants, it showed some favorable effects (Alzheimer’s Association International Conference, 2022).”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Late application
What the sources say
- Not checked yetcites Alzheimer’s Association International Conference, 2022
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“The data showed that gantenerumab had a positive impact on the reduction of cortical amyloid, leading to its further study by an exploratory open-label extension (OLE).338”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Late application
What the sources say
- Not checked yetcites [338] Salloway, S. et al. A trial of gantenerumab or solanezumab in dominantly inherited Alzheimer’s disease. Nat. Med. 27, 1187–1196 (2021). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“antibodies with Fc fragment reduced Aβ burden but also induced the engulgment of neuronal synapses by activating complement receptor 3 (CR3) or Fcγ receptor IIB (FcγRIIB), which exacerbates cognitive impairment in AD mice.440”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Insufficient specificity
What the sources say
- Not checked yetcites [440] Sun, X. Y. et al. Fc effector of anti-Abeta antibody induces synapse loss and cognitive deficits in Alzheimer’s disease-like mouse model. Signal Transduct. Target Ther. 8, 30 (2023). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“AD model mice with ATG7 KO showed deficient autophagy associated with drastically reduced extracellular Aβ plaques and markedly accumulated intraneuronal Aβ, suggesting that Aβ secretion was compromised due to the impaired autophagy.495,496”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > Perspective and future direction > Combination therapy and mechanism-based therapy
What the sources say
- Not checked yetcites [495] Nilsson, P. et al. Abeta secretion and plaque formation depend on autophagy. Cell Rep. 5, 61–69 (2013). source
- Not checked yetcites [496] Nilsson, P. et al. Autophagy-related protein 7 deficiency in amyloid beta (Abeta) precursor protein transgenic mice decreases Abeta in the multivesicular bodies and induces Abeta accumulation in the Golgi. Am. J. Pathol. 185, 305–313 (2015). source
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“A recent study also suggests that depressive symptoms in middle-aged individuals correlates with time to onset of cognitive decline, suggesting the role of psychiatric disorders as early markers of Alzheimer’s disease.556”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > Perspective and future direction > Identification of early Alzheimer’s biomarkers
What the sources say
- Not checked yetcites [556] Chan, C. K. et al. Depressive symptoms and CSF Alzheimer’s disease biomarkers in relation to clinical symptom onset of mild cognitive impairment. Alzheimers Dement (Amst.) 12, e12106 (2020).
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Unlike cell models, AD brain organoids are capable of generating the blood-brain barrier (BBB) as well as connections with other organs.535”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > Perspective and future direction > Patient-based research models
What the sources say
- Not checked yetcites [535] Cazzaniga, A., Fedele, G., Castiglioni, S. & Maier, J. A. The presence of blood-brain barrier modulates the response to magnesium salts in human brain organoids. Int J. Mol. Sci. 23, 5133 (2022). source
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In the paper
“Three-dimensional brain organoids derived from human pluripotent stem cells (hPSCs) have shown significant advantages in modeling neurological disorders including autism, microcephaly and Parkinson’s disease.528–530”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > Perspective and future direction > Patient-based research models
What the sources say
- Not checked yetcites [528] Lancaster, M. A. et al. Cerebral organoids model human brain development and microcephaly. Nature 501, 373–379 (2013). source
- Not checked yetcites [529] Chan, W. K., Griffiths, R., Price, D. J. & Mason, J. O. Cerebral organoids as tools to identify the developmental roots of autism. Mol. Autism 11, 58 (2020). source
- Not checked yetcites [530] Smits, L. M. et al. Modeling Parkinson’s disease in midbrain-like organoids. NPJ Parkinsons Dis. 5, 5 (2019). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“the CSF neurogranin increases exclusively in AD patients and has not been observed in other neurodegenerative disorders, such as frontotemporal dementia or Parkinson’s disease.550”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > Perspective and future direction > Identification of early Alzheimer’s biomarkers
What the sources say
- Not checked yetcites [550] Wellington, H. et al. Increased CSF neurogranin concentration is specific to Alzheimer disease. Neurology 86, 829–835 (2016). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“AβOs directly disturb the activity of NMDARs and impair NMDAR-mediated signaling pathways (e.g. Wnt/β-catenin signaling pathway), leading to synaptic loss and the reduction of spinal density.79”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The history of amyloid cascade hypothesis (Fig. 2) > Pathological role of Aβ aggregates (Fig. 3)
What the sources say
- Not checked yetcites [79] Magdesian, M. H. et al. Amyloid-beta binds to the extracellular cysteine-rich domain of Frizzled and inhibits Wnt/beta-catenin signaling. J. Biol. Chem. 283, 9359–9368 (2008). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“AβOs induce AMPAR ubiquitination and degradation, leading to the loss of AMPARs followed by the suppression of synaptic transmission.85,86”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The history of amyloid cascade hypothesis (Fig. 2) > Pathological role of Aβ aggregates (Fig. 3)
What the sources say
- Not checked yetcites [85] Hsieh, H. et al. AMPAR removal underlies Abeta-induced synaptic depression and dendritic spine loss. Neuron 52, 831–843 (2006). source
- Not checked yetcites [86] Zhang, Y., Guo, O., Huo, Y., Wang, G. & Man, H. Y. Amyloid-beta Induces AMPA Receptor Ubiquitination and Degradation in Primary Neurons and Human Brains of Alzheimer’s Disease. J. Alzheimers Dis. 62, 1789–1801 (2018). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Hardy and Higgins then proposed “the amyloid cascade hypothesis” in 1992, positing that Aβ deposits in the brain are the initiating event of AD pathogenesis, resulting in subsequent tau tangle formation, neuronal loss and dysfunction as well as cognitive decline.2”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The history of amyloid cascade hypothesis (Fig. 2)
What the sources say
- Not checked yetcites [2] Hardy, J. A. & Higgins, G. A. Alzheimer’s disease: the amyloid cascade hypothesis. Science 256, 184–185 (1992). source
plaindirect- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim.
In the paper
“growing evidence supports that the Aβ oligomers exist and exert their neurotoxicity independently of mature fibrils.61”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The history of amyloid cascade hypothesis (Fig. 2) > Pathological role of Aβ aggregates (Fig. 3)
What the sources say
- Not checked yetcites [61] Lambert, M. P. et al. Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins. Proc. Natl Acad. Sci. USA 95, 6448–6453 (1998). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In AD, the structural integrity of the blood-CSF barrier is destroyed, resulting in aberrant Aβ clearance.29”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > Introduction
What the sources say
- Not checked yetcites [29] Silverberg, G. D., Mayo, M., Saul, T., Rubenstein, E. & McGuire, D. Alzheimer’s disease, normal-pressure hydrocephalus, and senescent changes in CSF circulatory physiology: a hypothesis. Lancet Neurol. 2, 506–511 (2003). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“an APP mutation identified in the Icelandic population reduces Aβ production, leading to protection against cognitive decline in the elderly.40”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > Introduction
What the sources say
- Not checked yetcites [40] Jonsson, T. et al. A mutation in APP protects against Alzheimer’s disease and age-related cognitive decline. Nature 488, 96–99 (2012). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“AβOs destroy Glu-recycling at the synapse by increasing glutamate release, reducing glutamate uptake and impairing glutamate transporters, which causes the overactivation of extrasyaptic NMDARs, ultimately leading to LTP suppression, LTD enhancement, and synaptic loss.80”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The history of amyloid cascade hypothesis (Fig. 2) > Pathological role of Aβ aggregates (Fig. 3)
What the sources say
- Not checked yetcites [80] Li, S. et al. Soluble Abeta oligomers inhibit long-term potentiation through a mechanism involving excessive activation of extrasynaptic NR2B-containing NMDA receptors. J. Neurosci. 31, 6627–6638 (2011). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“It has been identified that the expressions of the two blood efflux transporters LRP1 and ABCB1 were reduced during AD, whereas the expression of the blood influx transporter RAGE is elevated.21,25”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > Introduction
What the sources say
- Not checked yetcites [21] Sweeney, M. D., Sagare, A. P. & Zlokovic, B. V. Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders. Nat. Rev. Neurol. 14, 133–150 (2018). source
- Not checked yetcites [25] Zlokovic, B. V. The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron 57, 178–201 (2008). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“This series of positive results offers a fresh hope and indicates that Aβ-based therapy may be indeed the right direction to be followed.”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > Introduction
hedgedconditional- Asserted: passes — The authors put it forward as true.
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Probably not a substantial claim. It may be too vague to check against evidence.
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In the paper
“ANAVEX®2-73 (Blarcamesine), which targets sigma-1 and M1 muscarinic receptors, has also demonstrated its disease-modifying activity in AD transgenic mice (3xTg-AD), including reducing amyloid and tau pathologies as well as improving cognitive deficits.51,52”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > Introduction
What the sources say
- Not checked yetcites [51] Lahmy, V. et al. Blockade of Tau hyperphosphorylation and Abeta(1)(-)(4)(2) generation by the aminotetrahydrofuran derivative ANAVEX2-73, a mixed muscarinic and sigma(1) receptor agonist, in a nontransgenic mouse model of Alzheimer’s disease. Neuropsychopharmacology 38, 1706–1723 (2013). source
- Not checked yetcites [52] Hampel, H. et al. A precision medicine framework using artificial intelligence for the identification and confirmation of genomic biomarkers of response to an Alzheimer’s disease therapy: Analysis of the blarcamesine (ANAVEX2-73) Phase 2a clinical study. Alzheimers Dement (N. Y.) 6, e12013 (2020). source
boosteddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
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In the paper
“Aβ aggregates can directly interact with the lipid and cholesterol components of the cell membrane, forming channels and destroying membrane integrity and permeability, which allows Ca2+ entering into the cell, leading to LTP inhibition and neuronal death.62,63”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The history of amyloid cascade hypothesis (Fig. 2) > Pathological role of Aβ aggregates (Fig. 3)
What the sources say
- Not checked yetcites [62] Bode, D. C., Freeley, M., Nield, J., Palma, M. & Viles, J. H. Amyloid-beta oligomers have a profound detergent-like effect on lipid membrane bilayers, imaged by atomic force and electron microscopy. J. Biol. Chem. 294, 7566–7572 (2019). source
- Not checked yetcites [63] Yasumoto, T. et al. High molecular weight amyloid beta(1-42) oligomers induce neurotoxicity via plasma membrane damage. FASEB J. 33, 9220–9234 (2019). source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Partial or completed deletion of TREM2 markedly reduced the number of Aβ-associated macrophages and increased cerebral Aβ plaques in AD model mice.174,175,178”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The history of amyloid cascade hypothesis (Fig. 2) > Pathological role of Aβ aggregates (Fig. 3)
What the sources say
- Not checked yetcites [174] Jay, T. R. et al. TREM2 deficiency eliminates TREM2+ inflammatory macrophages and ameliorates pathology in Alzheimer’s disease mouse models. J. Exp. Med 212, 287–295 (2015). source
- Not checked yetcites [175] Ulrich, J. D. et al. Altered microglial response to Abeta plaques in APPPS1-21 mice heterozygous for TREM2. Mol. Neurodegener. 9, 20 (2014). source
- Not checked yetcites [178] Jay, T. R. et al. Disease progression-dependent effects of TREM2 deficiency in a mouse model of Alzheimer’s disease. J. Neurosci. 37, 637–647 (2017). source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
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In the paper
“Considering the greater availability of blood sampling, blood-based biomarkers become the primary goal in screening for and diagnosing AD in the population and many studies now focus on examining the role of peripheral Aβ and APP in AD development.267–269”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The history of amyloid cascade hypothesis (Fig. 2) > Discovery and development of Aβ-based biomarkers
What the sources say
- Not checked yetcites [267] Halle, M. et al. Methods to monitor monocytes-mediated amyloid-beta uptake and phagocytosis in the context of adjuvanted immunotherapies. J. Immunol. Methods 424, 64–79 (2015). source
- Not checked yetcites [268] Frenkel, D. et al. Scara1 deficiency impairs clearance of soluble amyloid-beta by mononuclear phagocytes and accelerates Alzheimer’s-like disease progression. Nat. Commun. 4, 2030 (2013). source
- Not checked yetcites [269] Cheng, Y., Tian, D. Y. & Wang, Y. J. Peripheral clearance of brain-derived Abeta in Alzheimer’s disease: pathophysiology and therapeutic perspectives. Transl. Neurodegener. 9, 16 (2020). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Aβ produced by neurons induced the complement protein C3a released by astrocytes via NFκB signaling, which interacted with the receptors (C3aRs) on microglia and neurons to aggravate Aβ aggregate loads and cognitive impairment.191”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The history of amyloid cascade hypothesis (Fig. 2) > Pathological role of Aβ aggregates (Fig. 3)
What the sources say
- Not checked yetcites [191] Lian, H. et al. Astrocyte-microglia cross talk through complement activation modulates amyloid pathology in mouse models of Alzheimer’s disease. J. Neurosci. 36, 577–589 (2016). source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
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In the paper
“Both biomarkers have been demonstrated to have high diagnostic and prognostic value as they start changing decades before the onset of dementia symptoms.259–266”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The history of amyloid cascade hypothesis (Fig. 2) > Discovery and development of Aβ-based biomarkers
What the sources say
- Not checked yetcites [259] Jack, C. R. Jr. Advances in Alzheimer’s disease research over the past two decades. Lancet Neurol. 21, 866–869 (2022). source
- Not checked yetcites [260] Pike, K. E. et al. Beta-amyloid imaging and memory in non-demented individuals: evidence for preclinical Alzheimer’s disease. Brain 130, 2837–2844 (2007). source
- Not checked yetcites [261] Rowe, C. C. et al. Predicting Alzheimer disease with beta-amyloid imaging: results from the Australian imaging, biomarkers, and lifestyle study of ageing. Ann. Neurol. 74, 905–913 (2013). source
- Not checked yetcites [262] Blennow, K., Mattsson, N., Scholl, M., Hansson, O. & Zetterberg, H. Amyloid biomarkers in Alzheimer’s disease. Trends Pharm. Sci. 36, 297–309 (2015). source
- Not checked yetcites [263] Shaw, L. M. et al. Qualification of the analytical and clinical performance of CSF biomarker analyses in ADNI. Acta Neuropathol. 121, 597–609 (2011). source
- Not checked yetcites [264] Villemagne, V. L. et al. Amyloid beta deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer’s disease: a prospective cohort study. Lancet Neurol. 12, 357–367 (2013). source
- Not checked yetcites [265] Toledo, J. B., Shaw, L. M. & Trojanowski, J. Q. Plasma amyloid beta measurements - a desired but elusive Alzheimer’s disease biomarker. Alzheimers Res Ther. 5, 8 (2013). source
- Not checked yetcites [266] Jack, C. R. Jr. & Holtzman, D. M. Biomarker modeling of Alzheimer’s disease. Neuron 80, 1347–1358 (2013). source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Reduced DMN connectivity only occurs in individuals with elevated baseline Aβ-PET indexes, accelerating cortical atrophy.241”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The history of amyloid cascade hypothesis (Fig. 2) > Pathological role of Aβ aggregates (Fig. 3)
What the sources say
- Not checked yetcites [241] Hampton, O. L. et al. Resting-state functional connectivity and amyloid burden influence longitudinal cortical thinning in the default mode network in preclinical Alzheimer’s disease. Neuroimage Clin. 28, 102407 (2020). source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Redox active metal ions, such as Cu and Fe bind to Aβ to produce the ROS, which contributes to the oxidative damage on proteins and lipids leading to impaired membrane integrity, neuronal dysfunction and DNA damage.217–220”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The history of amyloid cascade hypothesis (Fig. 2) > Pathological role of Aβ aggregates (Fig. 3)
What the sources say
- Not checked yetcites [217] Smith, M. A., Harris, P. L., Sayre, L. M. & Perry, G. Iron accumulation in Alzheimer disease is a source of redox-generated free radicals. Proc. Natl Acad. Sci. USA 94, 9866–9868 (1997). source
- Not checked yetcites [218] Mao, P. & Reddy, P. H. Aging and amyloid beta-induced oxidative DNA damage and mitochondrial dysfunction in Alzheimer’s disease: implications for early intervention and therapeutics. Biochim Biophys. Acta 1812, 1359–1370 (2011). source
- Not checked yetcites [219] Nakamura, M. et al. Three histidine residues of amyloid-beta peptide control the redox activity of copper and iron. Biochemistry 46, 12737–12743 (2007). source
- Not checked yetcites [220] Bousejra-ElGarah, F., Bijani, C., Coppel, Y., Faller, P. & Hureau, C. Iron(II) binding to amyloid-beta, the Alzheimer’s peptide. Inorg. Chem. 50, 9024–9030 (2011). source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Aβ aggregates interact with glutamatergic neurotransmission, which impairs excitatory synaptic plasticity, leading to cognitive decline.222–225”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The history of amyloid cascade hypothesis (Fig. 2) > Pathological role of Aβ aggregates (Fig. 3)
What the sources say
- Not checked yetcites [222] Snyder, E. M. et al. Regulation of NMDA receptor trafficking by amyloid-beta. Nat. Neurosci. 8, 1051–1058 (2005). source
- Not checked yetcites [223] Busche, M. A. et al. Clusters of hyperactive neurons near amyloid plaques in a mouse model of Alzheimer’s disease. Science 321, 1686–1689 (2008). source
- Not checked yetcites [224] Malinow, R. New developments on the role of NMDA receptors in Alzheimer’s disease. Curr. Opin. Neurobiol. 22, 559–563 (2012). source
- Not checked yetcites [225] Brito-Moreira, J. et al. Abeta oligomers induce glutamate release from hippocampal neurons. Curr. Alzheimer Res 8, 552–562 (2011). source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“AβOs induce tau hyperphosphorylation and accumulation in dendritic spine, which further lead to synaptic loss and dysfunction.94,95”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The history of amyloid cascade hypothesis (Fig. 2) > Pathological role of Aβ aggregates (Fig. 3)
What the sources say
- Not checked yetcites [94] Tai, H. C. et al. Frequent and symmetric deposition of misfolded tau oligomers within presynaptic and postsynaptic terminals in Alzheimer’s disease. Acta Neuropathol. Commun. 2, 146 (2014).
- Not checked yetcites [95] Kaniyappan, S., Chandupatla, R. R., Mandelkow, E. M. & Mandelkow, E. Extracellular low-n oligomers of tau cause selective synaptotoxicity without affecting cell viability. Alzheimers Dement 13, 1270–1291 (2017). source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“EVP-0962 is another GSM that was shown to reduce Aβ42 levels and increase Aβ38 levels without affecting Notch signaling in vitro.”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > γ-secretase inhibitors/modulators
What the sources say
- Not checked yetcites [317] Rogers, K. et al. Modulation of gamma-secretase by EVP-0015962 reduces amyloid deposition and behavioral deficits in Tg2576 mice. Mol. Neurodegener. 7, 61 (2012). source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Avagacestat is a recently developed arylsulfonamide γ-secretase inhibitor with high selectivity for APP over Notch, which successfully reduces CSF Aβ levels in the animal models without any Notch-related toxicity.314”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > γ-secretase inhibitors/modulators
What the sources say
- Not checked yetcites [314] Albright, C. F. et al. Pharmacodynamics of selective inhibition of gamma-secretase by avagacestat. J. Pharm. Exp. Ther. 344, 686–695 (2013). source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Our group has also identified that circulating Aβ could pass the blood brain barrier (BBB) and enter the brain, contributing to the development of AD.”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The history of amyloid cascade hypothesis (Fig. 2) > Discovery and development of Aβ-based biomarkers
What the sources say
- Not checked yetcites [276] Bu, X. L. et al. Blood-derived amyloid-beta protein induces Alzheimer’s disease pathologies. Mol. Psychiatry 23, 1948–1956 (2018). source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Preclinical data showed that vanutide cridificar induced the generation of N-terminal anti-Aβ antibodies and successfully improved cognitive impairment in AD animal models.”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > Active and passive immunotherapy
What the sources say
- Not checked yetcites [322] Ryan, J. M. & Grundman, M. Anti-amyloid-beta immunotherapy in Alzheimer’s disease: ACC-001 clinical trials are ongoing. J. Alzheimers Dis. 17, 243 (2009). source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“there is increasing evidence to support that plasma Aβ acts as an endophenotype of AD, which simultaneously changes with Aβ status in the brain.”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The history of amyloid cascade hypothesis (Fig. 2) > Discovery and development of Aβ-based biomarkers
What the sources say
- Not checked yetcites [271] Palmqvist, S. et al. Cerebrospinal fluid and plasma biomarker trajectories with increasing amyloid deposition in Alzheimer’s disease. EMBO Mol. Med 11, e11170 (2019). source
- Not checked yetcites [272] Palmqvist, S. et al. Performance of Fully Automated Plasma Assays as Screening Tests for Alzheimer Disease-Related beta-Amyloid Status. JAMA Neurol. 76, 1060–1069 (2019). source
- Not checked yetcites [273] Damotte, V. et al. Plasma amyloid beta levels are driven by genetic variants near APOE, BACE1, APP, PSEN2: A genome-wide association study in over 12,000 non-demented participants. Alzheimers Dement 17, 1663–1674 (2021). source
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“The blood levels of APP669-711/Aβ42 and Aβ40/Aβ42 ratios, as well as peripheral Aβ-bound extracellular vesicles (EVs), have been shown to predict brain Aβ burden.”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The history of amyloid cascade hypothesis (Fig. 2) > Discovery and development of Aβ-based biomarkers
What the sources say
- Not checked yetcites [274] Nakamura, A. et al. High performance plasma amyloid-beta biomarkers for Alzheimer’s disease. Nature 554, 249–254 (2018). source
- Not checked yetcites [275] Yuyama, K. et al. Immuno-digital invasive cleavage assay for analyzing Alzheimer’s amyloid ss-bound extracellular vesicles. Alzheimers Res Ther. 14, 140 (2022). source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Besides LY2886721, many other candidates have also reached late stages of clinical trials, including atabecestat (Phase 2/3),305 elenbecestat (Phase 3),306 lanabecestat (Phase 2/3)307,308 and umibecestat (Phase 2/3).309 However, all of them have failed to receive final approval to reach the market.”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > BACE1 inhibitors
What the sources say
- Not checked yetcites [305] Sperling, R. et al. Findings of efficacy, safety, and biomarker outcomes of atabecestat in preclinical Alzheimer disease: A truncated randomized phase 2b/3 clinical trial. JAMA Neurol. 78, 293–301 (2021). source
- Not checked yetcites [306] Madrasi, K. et al. Systematic in silico analysis of clinically tested drugs for reducing amyloid-beta plaque accumulation in Alzheimer’s disease. Alzheimers Dement 17, 1487–1498 (2021). source
- Not checked yetcites [307] Sakamoto, K. et al. BACE1 inhibitor lanabecestat (AZD3293) in a phase 1 study of healthy Japanese subjects: Pharmacokinetics and effects on plasma and cerebrospinal fluid abeta peptides. J. Clin. Pharm. 57, 1460–1471 (2017). source
- Not checked yetcites [308] Zimmer, J. A. et al. Lanabecestat: Neuroimaging results in early symptomatic Alzheimer’s disease. Alzheimers Dement (N. Y) 7, e12123 (2021). source
- Not checked yetcites [309] Neumann, U. et al. The BACE-1 inhibitor CNP520 for prevention trials in Alzheimer’s disease. EMBO Mol. Med. 10, e9316 (2018). source
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“According to ALZFORUM (March 2023, www.alzforum.org), 298 AD therapies have been under clinical trials.”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy
What the sources say
- Not checked yetcites ALZFORUM
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“In contrast, Aβ peptides in the CNS can also move into the circulatory system, where the peptides are phagocytosed by the monocytes or neutrophils, directly degraded by the enzymes, or further transported to the peripheral organs or tissues for degradation or excretion.”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The history of amyloid cascade hypothesis (Fig. 2) > Discovery and development of Aβ-based biomarkers
What the sources say
- Not checked yetcites [28] Tarasoff-Conway, J. M. et al. Clearance systems in the brain-implications for Alzheimer disease. Nat. Rev. Neurol. 11, 457–470 (2015). source
- Not checked yetcites [277] Wang, J., Gu, B. J., Masters, C. L. & Wang, Y. J. A systemic view of Alzheimer disease - insights from amyloid-beta metabolism beyond the brain. Nat. Rev. Neurol. 13, 612–623 (2017). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“A recent study found that treatment with one potential candidate, SGSM-36, which successfully reduced the level of toxic Aβ42 peptides, without changing the proteolytic processing of Notch or α- and β-secretase processing of APP.316”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > γ-secretase inhibitors/modulators
What the sources say
- Not checked yetcites [316] Raven, F. et al. Soluble gamma-secretase modulators attenuate Alzheimer’s beta-amyloid pathology and induce conformational changes in presenilin 1. EBioMedicine 24, 93–101 (2017). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“In 2012, Eli Lilly announced that the application of LY2886721 produced the expected results in Phase 1 studies with reduced CSF levels of Aβ40 and Aβ42 as well as increased sAPPα levels (P3-359, Alzheimer’s Association International Conference, 2012).”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > BACE1 inhibitors
What the sources say
- Not checked yetcites P3-359, Alzheimer’s Association International Conference, 2012
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“UB-311 was shown to neutralize Aβ toxicity and enhance plaque clearance in preclinical studies.327”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > Active and passive immunotherapy
What the sources say
- Not checked yetcites [327] Wang, C. Y. et al. Site-specific UBITh amyloid-beta vaccine for immunotherapy of Alzheimer’s disease. Vaccine 25, 3041–3052 (2007). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Although the aggregates have been considered to be toxic, soluble Aβ at physiological levels have been identified to have biological functions, including enhancement of long-term potentiation (LTP),355–358 stimulation of neuronal differentiation,359 improvement of the brain’s ability to recover from injuries,360–363 inhibition of oxidative stress,364 antimicrobial activity365 and tumor suppression”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [355] Cirrito, J. R. et al. Synaptic activity regulates interstitial fluid amyloid-beta levels in vivo. Neuron 48, 913–922 (2005). source
- Not checked yetcites [356] Abramov, E. et al. Amyloid-beta as a positive endogenous regulator of release probability at hippocampal synapses. Nat. Neurosci. 12, 1567–1576 (2009). source
- Not checked yetcites [357] Morley, J. E. et al. A physiological role for amyloid-beta protein:enhancement of learning and memory. J. Alzheimers Dis. 19, 441–449 (2010). source
- Not checked yetcites [358] Dineley, K. T., Bell, K. A., Bui, D. & Sweatt, J. D. beta -Amyloid peptide activates alpha 7 nicotinic acetylcholine receptors expressed in Xenopus oocytes. J. Biol. Chem. 277, 25056–25061 (2002). source
- Not checked yetcites [359] Chen, Y. & Dong, C. Abeta40 promotes neuronal cell fate in neural progenitor cells. Cell Death Differ. 16, 386–394 (2009). source
- Not checked yetcites [360] Scott, G. et al. Amyloid pathology and axonal injury after brain trauma. Neurology 86, 821–828 (2016). source
- Not checked yetcites [361] Bird, S. M. et al. Cerebral amyloid-beta accumulation and deposition following traumatic brain injury-A narrative review and meta-analysis of animal studies. Neurosci. Biobehav Rev. 64, 215–228 (2016). source
- Not checked yetcites [362] Mannix, R. C., Zhang, J., Berglass, J., Qui, J. & Whalen, M. J. Beneficial effect of amyloid beta after controlled cortical impact. Brain Inj. 27, 743–748 (2013). source
- Not checked yetcites [363] Clarke, J. et al. Overexpression of APP provides neuroprotection in the absence of functional benefit following middle cerebral artery occlusion in rats. Eur. J. Neurosci. 26, 1845–1852 (2007). source
- Not checked yetcites [364] Kontush, A. et al. Amyloid-beta is an antioxidant for lipoproteins in cerebrospinal fluid and plasma. Free Radic. Biol. Med 30, 119–128 (2001). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Unfortunately, most of the initial trials including the prevention trial failed to achieve their primary endpoints, and crenezumab is now discontinued.”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > Active and passive immunotherapy
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“In the preclinical studies, ACI-24 was shown to generate high titers of anti-Aβ IgG1 and IgG2b antibodies and improve novel object recognition in AD mice.324”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > Active and passive immunotherapy
What the sources say
- Not checked yetcites [324] Davtyan, H. et al. Immunogenicity, efficacy, safety, and mechanism of action of epitope vaccine (Lu AF20513) for Alzheimer’s disease: prelude to a clinical trial. J. Neurosci. 33, 4923–4934 (2013). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Donanemab is a humanized IgG1 monoclonal antibody targeting the existing amyloid plaques and clearing them from the brain.344”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > Active and passive immunotherapy
What the sources say
- Not checked yetcites [344] Demattos, R. B. et al. A plaque-specific antibody clears existing beta-amyloid plaques in Alzheimer’s disease mice. Neuron 76, 908–920 (2012). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“The results were just published and showed that patients with lecanemab treatment had lower brain amyloid levels and reduced cognitive and functional decline as measured by the Clinical Dementia Rating-Sum of Boxes (CDR-SB), which quantifies symptom severity across a range of cognitive and function domains, by 27% compared with placebo.50”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > Active and passive immunotherapy
What the sources say
- Not checked yetcites [50] van Dyck, C. H. et al. Lecanemab in early Alzheimer’s disease. N. Engl. J. Med. 388, 9–21 (2023). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Later, Biogen announced that the interim futility analysis was wrong and the highest dose of aducanumab treatment significantly improved cognitive deficit in the participants (Oct 2019 news, investors.biogen.com).”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > Active and passive immunotherapy
What the sources say
- Not checked yetcites Oct 2019 news, investors.biogen.com
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Currently, four vaccines are under the clinical trials, including ALZ-101 (Phase 1), ACI-24 (Phase 2), ABvac 40 (Phase 2) and UB311 (Phase 3).”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > Active and passive immunotherapy
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“In the preclinical studies, 3D6 binds to monomeric, oligomeric and fibril forms of Aβ, leading to the reduced levels of Aβ and improved cognitive deficits in AD model mice.334”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > Active and passive immunotherapy
What the sources say
- Not checked yetcites [334] Bard, F. et al. Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat. Med. 6, 916–919 (2000). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“In the Phase 2 trial, it had been identified to successfully reduce brain amyloid and improved cognitive decline in the highest-dose group (twice-monthly 10 mg/kg).351”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > Active and passive immunotherapy
What the sources say
- Not checked yetcites [351] Swanson, C. J. et al. A randomized, double-blind, phase 2b proof-of-concept clinical trial in early Alzheimer’s disease with lecanemab, an anti-Abeta protofibril antibody. Alzheimers Res Ther. 13, 80 (2021). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Gantenerumab treatment significantly reduced the amyloid loads and normalized CSF Aβ42 levels.338”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > Active and passive immunotherapy
What the sources say
- Not checked yetcites [338] Salloway, S. et al. A trial of gantenerumab or solanezumab in dominantly inherited Alzheimer’s disease. Nat. Med. 27, 1187–1196 (2021). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Lecanemab (BAN2401) is the humanized IgG1 version of the mouse mAb158, which specifically binds to large, soluble Aβ protofibrils.”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > Active and passive immunotherapy
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Humanized antibodies are generated by modifying protein sequences from non-human species to increase their similarity to natural antibody variants produced in humans, which reduce the immunogenicity of the antibodies, enhance human effector functions, and increase the serum half-life of the antibodies in humans.330”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > Active and passive immunotherapy
What the sources say
- Not checked yetcites [330] Waldmann, H. Human monoclonal antibodies: The benefits of humanization. Methods Mol. Biol. 1904, 1–10 (2019). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“Another vaccine called ABvac40 targets the C-terminus of Aβ peptides and is also currently being evaluated in Phase 2 clinical studies.326”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > Active and passive immunotherapy
What the sources say
- Not checked yetcites [326] Lacosta, A. M. et al. Safety, tolerability and immunogenicity of an active anti-Abeta40 vaccine (ABvac40) in patients with Alzheimer’s disease: a randomised, double-blind, placebo-controlled, phase I trial. Alzheimers Res. Ther. 10, 12 (2018). source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“In the Phase 2 studies, UB-311 also showed its safety and generated Aβ antibodies in 96% of the patients with mild AD (14th International Conference on Alzheimer’s and Parkinson’s Disease, 2019).”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > Active and passive immunotherapy
What the sources say
- Not checked yetcites 14th International Conference on Alzheimer’s and Parkinson’s Disease, 2019
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“The antibody was found to be safe and well tolerated during the Phase 1 clinical trials, except that transient amyloid-related imaging abnormalities (ARIA) appeared in some patients given a high dosage.336”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > Active and passive immunotherapy
What the sources say
- Not checked yetcites [336] Klein, G. et al. Gantenerumab reduces amyloid-beta plaques in patients with prodromal to moderate Alzheimer’s disease: a PET substudy interim analysis. Alzheimers Res Ther. 11, 101 (2019). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Although solanezumab was well tolerated in the participants, it was not able to show the significant therapeutic benefits to AD patients.345,346”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > Active and passive immunotherapy
What the sources say
- Not checked yetcites [345] Honig, L. S. et al. Trial of solanezumab for mild dementia due to Alzheimer’s disease. N. Engl. J. Med. 378, 321–330 (2018). source
- Not checked yetcites [346] Schwarz, A. J. et al. Magnetic resonance imaging measures of brain atrophy from the EXPEDITION3 trial in mild Alzheimer’s disease. Alzheimers Dement (N. Y.) 5, 328–337 (2019). source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“ACI-24 is a liposome vaccine based on the Aβ1-15 sequences. It is designed to generate antibodies specifically against the β-sheet folding of Aβ.”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > Active and passive immunotherapy
What the sources say
- Not checked yetcites [324] Davtyan, H. et al. Immunogenicity, efficacy, safety, and mechanism of action of epitope vaccine (Lu AF20513) for Alzheimer’s disease: prelude to a clinical trial. J. Neurosci. 33, 4923–4934 (2013). source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Just several months ago (Nov 14, 2022), Roche and Genentech announced that the outcome of the Phase 3 trials were disappointing, in which the drugs failed to slow cognitive impairment.”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > Active and passive immunotherapy
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
The quote only partly states this claim.
In the paper
“genetic deletion of APP significantly aggravated the severity of the disease, suggesting the protective role of Aβ against autoimmune inflammation in CNS.397”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [397] Grant, J. L. et al. Reversal of paralysis and reduced inflammation from peripheral administration of beta-amyloid in TH1 and TH17 versions of experimental autoimmune encephalomyelitis. Sci. Transl. Med 4, 145ra105 (2012). source
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These findings suggest that physiological levels of Aβ monomers are crucial to maintain a normal synaptic function while only Aβ aggregates have the inhibitory and toxic effects.”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Evidence from patients and animal models also shows rapidly increased Aβ expressions after being injured are beneficial,360–363 indicating the role of Aβ in stimulating the brain to recover from traumatic and ischemic injuries.”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [360] Scott, G. et al. Amyloid pathology and axonal injury after brain trauma. Neurology 86, 821–828 (2016). source
- Not checked yetcites [361] Bird, S. M. et al. Cerebral amyloid-beta accumulation and deposition following traumatic brain injury-A narrative review and meta-analysis of animal studies. Neurosci. Biobehav Rev. 64, 215–228 (2016). source
- Not checked yetcites [362] Mannix, R. C., Zhang, J., Berglass, J., Qui, J. & Whalen, M. J. Beneficial effect of amyloid beta after controlled cortical impact. Brain Inj. 27, 743–748 (2013). source
- Not checked yetcites [363] Clarke, J. et al. Overexpression of APP provides neuroprotection in the absence of functional benefit following middle cerebral artery occlusion in rats. Eur. J. Neurosci. 26, 1845–1852 (2007). source
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“In the CNS, the nicotinic acetylcholine receptors (nAChRs) are expressed in both neurons and non-neuronal cells.379,380”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [379] Sudweeks, S. N. & Yakel, J. L. Functional and molecular characterization of neuronal nicotinic ACh receptors in rat CA1 hippocampal neurons. J. Physiol. 527, 515–528 (2000). source
- Not checked yetcites [380] Papouin, T., Dunphy, J. M., Tolman, M., Dineley, K. T. & Haydon, P. G. Septal cholinergic neuromodulation tunes the astrocyte-dependent gating of hippocampal NMDA receptors to wakefulness. Neuron 94, 840–854.e847 (2017). source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“In contrast, removal of endogenous Aβ by injection of anti-Aβ antibodies or genetic manipulation greatly decreased LTP and impaired memory, which could be rescued by the addition of human Aβ42.357,373–376”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [357] Morley, J. E. et al. A physiological role for amyloid-beta protein:enhancement of learning and memory. J. Alzheimers Dis. 19, 441–449 (2010). source
- Not checked yetcites [373] Seabrook, G. R. et al. Mechanisms contributing to the deficits in hippocampal synaptic plasticity in mice lacking amyloid precursor protein. Neuropharmacology 38, 349–359 (1999). source
- Not checked yetcites [374] Garcia-Osta, A. & Alberini, C. M. Amyloid beta mediates memory formation. Learn Mem. 16, 267–272 (2009). source
- Not checked yetcites [375] Puzzo, D. et al. Endogenous amyloid-beta is necessary for hippocampal synaptic plasticity and memory. Ann. Neurol. 69, 819–830 (2011). source
- Not checked yetcites [376] Galanis, C. et al. Amyloid-beta mediates homeostatic synaptic plasticity. J. Neurosci. 41, 5157–5172 (2021). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“α7-nAChRs are involved in a variety of biological functions, including neurotransmitter release, synaptic plasticity and neurogenesis.384,385”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [384] Letsinger, A. C., Gu, Z. & Yakel, J. L. alpha7 nicotinic acetylcholine receptors in the hippocampal circuit: taming complexity. Trends Neurosci. 45, 145–157 (2022). source
- Not checked yetcites [385] Townsend, M. et al. alpha7-nAChR agonist enhances neural plasticity in the hippocampus via a GABAergic circuit. J. Neurophysiol. 116, 2663–2675 (2016). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“In AD brain, nAChRs have been detected in Aβ42-positive neurons and their reduction is associated with disease progression.386”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [386] Nagele, R. G., D’Andrea, M. R., Anderson, W. J. & Wang, H. Y. Intracellular accumulation of beta-amyloid(1-42) in neurons is facilitated by the alpha 7 nicotinic acetylcholine receptor in Alzheimer’s disease. Neuroscience 110, 199–211 (2002). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Thus, α7-nAChR KO mice at 12-month-old showed Aβ elevation as a compensatory response of α7-nAChRs and exhibited AD-like pathologies.390”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [390] Tropea, M. R. et al. Genetic deletion of alpha7 nicotinic acetylcholine receptors induces an age-dependent Alzheimer’s disease-like pathology. Prog. Neurobiol. 206, 102154 (2021). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“As ligand-gated ion channels, nAChRs opened in response to the depolarization of the membrane, allowing Na+, K+ and Ca2+ to enter the cells.381,382”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [381] Castro, N. G. & Albuquerque, E. X. alpha-Bungarotoxin-sensitive hippocampal nicotinic receptor channel has a high calcium permeability. Biophys. J. 68, 516–524 (1995). source
- Not checked yetcites [382] Unwin, N. Nicotinic acetylcholine receptor and the structural basis of neuromuscular transmission: insights from Torpedo postsynaptic membranes. Q Rev. Biophys. 46, 283–322 (2013). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“The mechanism behind Aβ-induced α7-nAChR activation could be due to the disruption of intracellular signal transduction to stimulate the calcium influx.383”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [383] Dougherty, J. J., Wu, J. & Nichols, R. A. Beta-amyloid regulation of presynaptic nicotinic receptors in rat hippocampus and neocortex. J. Neurosci. 23, 6740–6747 (2003). source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Aβ42 cannot prevent the replication of non-enveloped human adenovirus, suggesting that it probably interacts with viral coat proteins.404”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [404] Bourgade, K. et al. beta-Amyloid peptides display protective activity against the human Alzheimer’s disease-associated herpes simplex virus-1. Biogerontology 16, 85–98 (2015). source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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It may state two separate claims as one.
In the paper
“a rapid generation and deposition of Aβ in stroke and after head trauma, which could benefit to maintain the BBB integrity and inhibit the leakage of serum components into the brain, leading to neuroinflammation.436”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Disturbed physiological functions of soluble Aβ
What the sources say
- Not checked yetcites [436] Roberts, G. W. et al. Beta amyloid protein deposition in the brain after severe head injury: implications for the pathogenesis of Alzheimer’s disease. J. Neurol. Neurosurg. Psychiatry 57, 419–425 (1994). source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“BACE2 is a close homolog of BACE1 but plays a neuroprotective role by inhibiting the amyloidogenic pathway of APP processing7,8,10 and reducing potassium channel Kv2.1-induced neuronal apoptosis.438”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Insufficient specificity
What the sources say
- Not checked yetcites [7] Deng, Y. et al. Amyloid-beta protein (Abeta) Glu11 is the major beta-secretase site of beta-site amyloid-beta precursor protein-cleaving enzyme 1(BACE1), and shifting the cleavage site to Abeta Asp1 contributes to Alzheimer pathogenesis. Eur. J. Neurosci. 37, 1962–1969 (2013). source
- Not checked yetcites [8] Zhang, S. et al. BACE1 cleavage site selection critical for amyloidogenesis and Alzheimer’s pathogenesis. J. Neurosci. 37, 6915–6925 (2017). source
- Not checked yetcites [10] Sun, X., He, G. & Song, W. BACE2, as a novel APP theta-secretase, is not responsible for the pathogenesis of Alzheimer’s disease in Down syndrome. FASEB J. 20, 1369–1376 (2006). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Although the human tau gene MAPT mutations per se only cause frontotemporal dementia (FTD) rather than AD,462 tau mediates Aβ toxicity to promote the pathological process of AD.92,137”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Lack of accurate animal models
What the sources say
- Not checked yetcites [462] D’Souza, I. et al. Missense and silent tau gene mutations cause frontotemporal dementia with parkinsonism-chromosome 17 type, by affecting multiple alternative RNA splicing regulatory elements. Proc. Natl. Acad. Sci. USA 96, 5598–5603 (1999). source
- Not checked yetcites [92] Ittner, L. M. et al. Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer’s disease mouse models. Cell 142, 387–397 (2010). source
- Not checked yetcites [137] Bloom, G. S. Amyloid-beta and tau: the trigger and bullet in Alzheimer disease pathogenesis. JAMA Neurol. 71, 505–508 (2014). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Less than 1% of all AD cases are early-onset with symptoms developed at an age of 50 s and earlier, and caused by gene mutations in APP, PSEN1 or PSEN2.7,38,39”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Lack of accurate animal models
What the sources say
- Not checked yetcites [7] Deng, Y. et al. Amyloid-beta protein (Abeta) Glu11 is the major beta-secretase site of beta-site amyloid-beta precursor protein-cleaving enzyme 1(BACE1), and shifting the cleavage site to Abeta Asp1 contributes to Alzheimer pathogenesis. Eur. J. Neurosci. 37, 1962–1969 (2013). source
- Not checked yetcites [38] Goate, A. et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature 349, 704–706 (1991). source
- Not checked yetcites [39] Zhang, S. et al. A presenilin-1 mutation causes Alzheimer disease without affecting Notch signaling. Mol. Psychiatry 25, 603–613 (2020). source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Growing evidence indicates that Aβ accumulation stimulates tau phosphorylation and fibrillary tangle formation, leading to the process of neurodegeneration.112–114”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > Perspective and future direction > Combination therapy and mechanism-based therapy
What the sources say
- Not checked yetcites [112] Ising, C. et al. NLRP3 inflammasome activation drives tau pathology. Nature 575, 669–673 (2019). source
- Not checked yetcites [113] Zhang, Y., Dong, Z. & Song, W. NLRP3 inflammasome as a novel therapeutic target for Alzheimer’s disease. Signal Transduct. Target Ther. 5, 37 (2020). source
- Not checked yetcites [114] He, Z. et al. Amyloid-beta plaques enhance Alzheimer’s brain tau-seeded pathologies by facilitating neuritic plaque tau aggregation. Nat. Med. 24, 29–38 (2018). source
hedgeddirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“More than 99% of AD cases occur at an age >60 years in a sporadic manner, potentiated by various risk factors related to lifestyle.442”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The stumbling block of anti-Aβ therapy > Lack of accurate animal models
What the sources say
- Not checked yetcites [442] Daviglus, M. L. et al. National Institutes of Health State-of-the-Science Conference statement: preventing alzheimer disease and cognitive decline. Ann. Intern Med 153, 176–181 (2010). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
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Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“APP and Aβ can be imported into mitochondria, where they can interact with mitochondrial components, impair ATP production, and increase oxidative damage.481,482”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > Perspective and future direction > Combination therapy and mechanism-based therapy
What the sources say
- Not checked yetcites [481] Spuch, C., Ortolano, S. & Navarro, C. New insights in the amyloid-Beta interaction with mitochondria. J. Aging Res. 2012, 324968 (2012). source
- Not checked yetcites [482] Wilkins, H. M. Interactions between amyloid, amyloid precursor protein, and mitochondria. Biochem Soc. Trans. 51, 173–182 (2023). source
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Biomarkers are needed for identifying patients with preclinical Alzheimer’s disease so that treatment such as mechanism-based therapy could prevent or slow down the disease.”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > Conclusions
plainconditional- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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Probably not a substantial claim. It may be too vague to check against evidence.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Combination therapy that targets different mechanisms and pathologies would be directed by biomarkers and customized to the individual.”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > Conclusions
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence. The paper may give no reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Most Aβ-targeting drug trials have failed as a consequence by lack of sufficient specificity and accurate translational models, loss of Aβ physiological homeostasis, and failure to be administered during the best therapeutic window.”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > Conclusions
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Since Aβ aggregates act as the unique specific pathological hallmark of AD and play a causative role in the disease development, they are believed as a promising target for Alzheimer’s modification.”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > Conclusions
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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Probably not a substantial claim. The paper may give no reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“It has been found that miRNAs are involved in Alzheimer’s pathogenesis and are easily detected in body fluids, including CSF, plasma and serum. Therefore, they become an attractive target for developing AD biomarkers.551,552”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > Perspective and future direction > Identification of early Alzheimer’s biomarkers
What the sources say
- Not checked yetcites [551] Dehghani, R., Rahmani, F. & Rezaei, N. MicroRNA in Alzheimer’s disease revisited: implications for major neuropathological mechanisms. Rev. Neurosci. 29, 161–182 (2018). source
- Not checked yetcites [552] Xia, X. et al. Exosomal miRNAs in central nervous system diseases: biomarkers, pathological mediators, protective factors and therapeutic agents. Prog. Neurobiol. 183, 101694 (2019). source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Since Aβ aggregates act as the unique specific pathological hallmark of AD and play a causative role in the disease development, they are believed as a promising target for Alzheimer’s modification.”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > Conclusions
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. The paper may give no reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Translational models and tools to mimic the nature of AD more closely are also required to bridge the gap between basic research and the clinical practice.”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > Conclusions
plain- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence.
The paper relies on this without support.
The single molecular assay (Simoa) allows measurement of Aβ40 and Aβ42 levels at sub-femtomolar concentration.
“Recently, the development of single molecular assay (Simoa), an ultra-sensitive immunoassay technology, allows the measurement of Aβ40 and Aβ42 levels at sub-femtomolar concentration.”
The paper relies on this without support.
The currently approved AD drugs can only help alleviate symptoms instead of modifying the disease.
“However, these drugs can only help alleviate the symptoms instead of modifying the disease.”
The paper relies on this without support.
38 of the Aβ-targeting therapies have been discontinued due to ineffectiveness or toxic side effects.
“So far, two antibody-based drugs aducanumab and lecanemab have been approved by the FDA and 38 of them have been discontinued due to ineffectiveness or toxic side effects.”
The paper relies on this without support.
All γ-secretase modulators have been discontinued in clinical trials.
“Unfortunately, all of them have been discontinued in the clinical trials.”
The paper relies on this without support.
The Aβ-mAb complex induces complement-dependent cytotoxicity, resulting in lysis of target cells.
“In addition, the Aβ-mAb complex induces the complement-dependent cytotoxicity, resulting in the lysis of the target cells.”
The paper relies on this without support.
Most traditional Chinese medicine treatments are derived from natural products with multi-target, multi-pathway capacity and mild adverse events.
“Most TCM treatment are derived from natural products with multi-target, multi-pathway capacity and mild adverse events.”
The paper relies on this without support.
Brain organoids can only be cultured within six months; otherwise volume shrinkage and cellular apoptosis occur because oxygen and nutrients cannot reach the innermost organoid regions.
“So far, brain organoids can only be cultured within six months, otherwise volume shrinkage and cellular apoptosis occur as neither the oxygen nor nutrients will be able to reach the innermost organoid regions.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“However, mounting evidence indicates that soluble oligomers, rather than insoluble fibrils, are the principal neurotoxic species, disrupting synaptic plasticity, impairing long-term potentiation, and triggering downstream inflammatory cascades [29].”
From Toward a Unified Framework in Molecular Neurobiology of Alzheimer’s Disease: Revisiting the Pathophysiological Hypotheses (2026) · cites this paper as [29]
Experimental — accuracy not yet measuredIn the citing paper
“Several clinical investigations focusing on Aβ have produced contradictory findings, casting doubt on the veracity of the amyloid theory in general.”
From Recent Advances in Therapeutics for the Treatment of Alzheimer’s Disease (2024) · cites this paper as [86]
In the citing paper
“While lowering Aβ levels can decrease cognitive deterioration, not all patients will definitely see improved clinical outcomes from this strategy, according to certain research [86,93].”
From Recent Advances in Therapeutics for the Treatment of Alzheimer’s Disease (2024) · cites this paper as [86]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > Active and passive immunotherapy
“Aducanumab is the first FDA-approved therapy for Alzheimer’s.”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy
“To date, five drugs have been approved for the treatment of AD.”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > Active and passive immunotherapy
“Currently, four vaccines are under the clinical trials, including ALZ-101 (Phase 1), ACI-24 (Phase 2), ABvac 40 (Phase 2) and UB311 (Phase 3).”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy
“AV-1959D | Intradermal injection | A DNA vaccine fuses coding sequences of three copies of Aβ1-11 to 12 to elicit antibodies to Aβ peptides | NCT05642429 (Phase 2)”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy
“Targeting Aβ monomers | Targeting Aβ monomers | Targeting Aβ monomers”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy > Active and passive immunotherapy
“Aducanumab is the first FDA-approved therapy for Alzheimer’s.47,48 It is a human IgG1 mAb against a conformational epitope found on the N-terminus of Aβ (residues 3–6), and thus specifically targeting aggregates rather than monomers.”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy
“To date, five drugs have been approved for the treatment of AD. Four of these medications are classified as cholinesterase inhibitors (CIs), including tacrine, donepezil, rivastigmine, and galantamine.”
§ Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future > The progression of Anti-Aβ therapy
“So far, two antibody-based drugs aducanumab and lecanemab have been approved by the FDA”
Citations
Cites
2 retracted
Items 201–400 of 559
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“Particularly notable is toxicity resulting from inhibition of Notch-1 cleavage, which disrupts essential signaling from this receptor.(15,313) Thus, we should discover compounds that act as substrate-selective γsecretase inhibitors, which block the cleavage of C99, the immediate precursor of Aβ, while allowing Notch c…”
BackgroundSelf-citationVascular, glial, and lymphatic immune gateways of the central nervous system
Engelhardt, B., Carare, R. O., Bechmann, I., Flügel, A., Laman, J. D., & Weller, R. O. (2016) · Acta Neuropathologica · doi:10.1007/s00401-016-1606-5 · Cited by 362 · cited 1×
“Similar to other brain metabolites, Aβ clearance depends on different pathways including enzyme degradation, crossing the blood–brain barrier (BBB), interstitial fluid (ISF) bulk-flow and CSF absorption.(19,20) The BBB is composed of endothelial cells connected by tight junctions to form a selectively permeable system.”
BackgroundA trial of gantenerumab or solanezumab in dominantly inherited Alzheimer’s disease
Salloway, S., Farlow, M., McDade, E., Clifford, D. B., Wang, G., Llibre-Guerra, J. J., Hitchcock, J. M., Mills, S. L., Santacruz, A. M., Aschenbrenner, A. J., et al. (2021) · Nature Medicine · doi:10.1038/s41591-021-01369-8 · Cited by 359 · cited 1×
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BackgroundStabilization of neurotoxic Alzheimer amyloid-β oligomers by protein engineering
Sandberg, A., Luheshi, L. M., Söllvander, S., Pereira de Barros, T., Macao, B., Knowles, T. P. J., Biverstål, H., Lendel, C., Ekholm-Petterson, F., Dubnovitsky, A., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1001740107 · Cited by 358
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“As with NMDARs, AMPARs are also the principal receptors mediating excitatory synaptic transmission.(230) It has been identified that APP overexpression and increase of soluble Aβ oligomers are related with the downregulation of GluA1/2 subunits of AMPARs, leading to the inhibition of synaptic plasticity, spine loss, a…”
BackgroundTranscriptional signature in microglia associated with Aβ plaque phagocytosis
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“In addition, mitochondrion-derived ROS modulated the APP processing and triggered Aβ production to form a vicous cycle.(221)”
BackgroundPalmqvist, S., Insel, P. S., Stomrud, E., Janelidze, S., Zetterberg, H., Brix, B., Eichenlaub, U., Dage, J. L., Chai, X., Blennow, K., et al. (2019) · EMBO Molecular Medicine · doi:10.15252/emmm.201911170 · Cited by 353
Can Alzheimer disease be prevented by amyloid-β immunotherapy?
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“Excessive Aβ peptides induced LTD by inhibiting LTP and making a shift of the NMDAR-dependent signaling cascades.(226) Thus, Aβ accumulation inhibited the synaptic transmission, resulting in early cognitive impairment.”
BackgroundAmyloid-Beta Protein Clearance and Degradation (ABCD) Pathways and their Role in Alzheimer’s Disease
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“In the hippocampus of AD patients, the enzymes IDE, ACE and NEP had decreased activity.(30) AD model mice also showed the impaired Aβ degradation system.”
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BackgroundOxidative stress mediates tau-induced neurodegeneration in Drosophila
Dias-Santagata, D., Fulga, T. A., Duttaroy, A., & Feany, M. B. (2007) · Journal of Clinical Investigation · doi:10.1172/jci28769 · Cited by 318
Adolfsson, O., Pihlgren, M., Toni, N., Varisco, Y., Buccarello, A. L., Antoniello, K., Lohmann, S., Piorkowska, K., Gafner, V., Atwal, J. K., et al. (2012) · Journal of Neuroscience · doi:10.1523/jneurosci.4742-11.2012 · Cited by 317
Mao, P., & Reddy, P. H. (2011) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2011.08.005 · Cited by 316
Tau Protein Is Required for Amyloid β-Induced Impairment of Hippocampal Long-Term Potentiation
Shipton, O. A., Leitz, J. R., Dworzak, J., Acton, C. E. J., Tunbridge, E. M., Denk, F., Dawson, H. N., Vitek, M. P., Wade-Martins, R., Paulsen, O., et al. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.2610-10.2011 · Cited by 315 · cited 1×
“It has been demonstrated that the absence of tau proteins prevent Aβ-induced LTP impairment mouse hippocampal slices.(102) Another study also indentified that reduction of tau could ameliorate Aβ-induced Ca influx into neurons and AD-related excitotoxicity in vivo.”
BackgroundFyn inhibition rescues established memory and synapse loss in Alzheimer mice
Kaufman, A. C., Salazar, S. V., Haas, L. T., Yang, J., Kostylev, M. A., Jeng, A. T., Robinson, S. A., Gunther, E. C., van Dyck, C. H., Nygaard, H. B., et al. (2015) · Annals of Neurology · doi:10.1002/ana.24394 · Cited by 314 · cited 1×
“Accordingly, inhibition of Fyn improved the cognitive deficits in transgenic mice with Aβ and tau depositions.(144,145) PET and CSF tests also indicate the synergy between Aβ and tau, which leads to brain dysfunction and cognitive impairment.”
BackgroundTau Oligomers: Cytotoxicity, Propagation, and Mitochondrial Damage
Shafiei, S. S., Guerrero-Muñoz, M. J., & Castillo-Carranza, D. L. (2017) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2017.00083 · Cited by 314 · cited 1×
“Aβ triggered caspase-3 (CASP3)-induced cleavage of tau at Asp421 to yield an N-terminal product, which self-aggregated and further assembled into neurotoxic oligomers.(134,135) Tau oligomers not only led to neuronal damage but also bound to astrocytes and microglia to induce neuroinflammation.”
BackgroundLongitudinal cognitive and biomarker changes in dominantly inherited Alzheimer disease
McDade, E., Wang, G., Gordon, B. A., Hassenstab, J., Benzinger, T. L. S., Buckles, V., Fagan, A. M., Holtzman, D. M., Cairns, N. J., Goate, A. M., et al. (2018) · Neurology · doi:10.1212/wnl.0000000000006277 · Cited by 314 · cited 1×
“A change in CSF Aβ levels can be detected even up to 25 years before a patient begins to show symptoms.(478) Thus, the current application of Aβ therapies may be too late for symptomatic patients, whose therapeutic window has already closed.”
BackgroundObesity‐related leptin regulates Alzheimer's Aβ
Fewlass, D. C., Noboa, K., Pi‐Sunyer, F. X., Johnston, J. M., Yan, S. D., & Tezapsidis, N. (2004) · The FASEB Journal · doi:10.1096/fj.04-2572com · Cited by 308
Zou, K., Gong, J.-S., Yanagisawa, K., & Michikawa, M. (2002) · The Journal of Neuroscience · doi:10.1523/jneurosci.22-12-04833.2002 · Cited by 305 · cited 1×
“Both Aβ40 and Aβ42 in physiological concentrations prevented lipoprotein oxidation in CSF and plasma.(364,421) In addition, the increased generation of Aβ by cells from Alzheimer’s patients with mutant PSEN1 was accompanied by a reduction of ROS levels.”
BackgroundAltered microglial response to Aβ plaques in APPPS1-21 mice heterozygous for TREM2
Ulrich, J. D., Finn, M. B., Wang, Y., Shen, A., Mahan, T. E., Jiang, H., Stewart, F. R., Piccio, L., Colonna, M., & Holtzman, D. M. (2014) · Molecular Neurodegeneration · doi:10.1186/1750-1326-9-20 · Cited by 302 · cited 2×
“Aβ plaques in AD model mice.(174,175,178) The reduction of TREM2 in Aβ-associated macrophages also altered astrocytosis detected by glial fibrillary acidic protein (GFAP) and S100β.”
BackgroundLogovinsky, V., Satlin, A., Lai, R. Y. K., Swanson, C. J., Kaplow, J. M., Osswald, G., Basun, H., & Lannfelt, L. (2016) · Alzheimer s Research & Therapy · doi:10.1186/s13195-016-0181-2 · Cited by 302
Benjannet, S., Elagoz, A., Wickham, L., Mamarbachi, M., Munzer, J. S., Basak, A., Lazure, C., Cromlish, J. A., Sisodia, S., Checler, F., et al. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m009899200 · Cited by 301
Qualification of the analytical and clinical performance of CSF biomarker analyses in ADNI
Initiative, T. A. D. N., Shaw, L. M. J., Vanderstichele, H., Knapik-Czajka, M. E., Figurski, M., Coart, E., Blennow, K., Soares, H. D., Simon, A. J., Lewczuk, P., et al. (2011) · Acta Neuropathologica · doi:10.1007/s00401-011-0808-0 · Cited by 301
Amyloid Activates GSK-3β to Aggravate Neuronal Tauopathy in Bigenic Mice
Terwel, D., Muyllaert, D., Dewachter, I., Borghgraef, P., Croes, S., Devijver, H., & Van Leuven, F. (2008) · The American Journal of Pathology · doi:10.2353/ajpath.2008.070904 · Cited by 300
Ahmed, Z., Sheng, H., Xu, Y.-F., Lin, W.-L., Innes, A. E., Gass, J. M., Yu, X., Hou, H., Chiba, S., Yamanouchi, K., et al. (2010) · American Journal Of Pathology · doi:10.2353/ajpath.2010.090915 · Cited by 299 · cited 1×
“Progranulin is a growth factor expressed in neurons and microglia, which modulates neuroinflammatory to reduce microgliosis and astrogliosis.(543) It has been observed that the CSF level of progranulin elevates as early as ten years before the presentation of symptoms in patients with familial or sporadic AD.”
BackgroundRetinal vascular biomarkers for early detection and monitoring of Alzheimer’s disease
Frost, S., Kanagasingam, Y., Sohrabi, H., Vignarajan, J., Bourgeat, P., Salvado, O., Villemagne, V, Rowe, C. C., Lance Macaulay, S., Szoeke, C., et al. (2013) · Translational Psychiatry · doi:10.1038/tp.2012.150 · Cited by 297
Bakker, A., Albert, M., Krauss, G. L., Speck, C. L., & Gallagher, M. (2015) · NeuroImage Clinical · doi:10.1016/j.nicl.2015.02.009 · Cited by 295
Xiong, H., Callaghan, D., Jones, A., Walker, D. G., Lue, L., Beach, T. G., Sue, L. I., Woulfe, J., Xu, H., Stanimirovic, D. B., et al. (2007) · Neurobiology of Disease · doi:10.1016/j.nbd.2007.10.005 · Cited by 293
Pan, R., Ma, J., Kong, X.-X., Wang, X., Li, S., Qi, X., Yan, Y., Cheng, J., Liu, Q., Jin, W., et al. (2019) · Science Advances · doi:10.1126/sciadv.aau6328 · Cited by 293
The AHEAD 3‐45 Study: Design of a prevention trial for Alzheimer's disease
Rafii, M. S., Sperling, R. A., Donohue, M. C., Zhou, J., Roberts, C., Irizarry, M. C., Dhadda, S., Sethuraman, G., Kramer, L. D., Swanson, C. J., et al. (2023) · Alzheimer's & Dementia · doi:10.1002/alz.12748 · Cited by 291 · cited 1×
“In Feb 2020, it was announced that a large lecanemab study called AHEAD3-45 would run from July 2020 to October 2027 to measure the preventive effect of lecanemab treatment on amyloid and tau tangle formation.(353)”
BackgroundRutin prevents tau pathology and neuroinflammation in a mouse model of Alzheimer’s disease
Sun, X., Li, L., Dong, Q.-X., Zhu, J., Huang, Y., Hou, S., Yu, X., & Liu, R. (2021) · Journal of Neuroinflammation · doi:10.1186/s12974-021-02182-3 · Cited by 290
Faller, P. (2009) · ChemBioChem · doi:10.1002/cbic.200900321 · Cited by 285
Potent amyloidogenicity and pathogenicity of Aβ43
Saito, T., Suemoto, T., Brouwers, N., Sleegers, K., Funamoto, S., Mihira, N., Matsuba, Y., Yamada, K., Nilsson, P., Takano, J., et al. (2011) · Nature Neuroscience · doi:10.1038/nn.2858 · Cited by 282
Seabrook, G. R., Smith, D. W., Bowery, B. J., Easter, A., Reynolds, T., Fitzjohn, S. M., Morton, R. A., Zheng, H., Dawson, G. R., SIRINATHSINGHJI, D. J. S., et al. (1999) · Neuropharmacology · doi:10.1016/s0028-3908(98)00204-4 · Cited by 281
Intracellular Aβ42 activates p53 promoter: a pathway to neurodegeneration in Alzheimer's disease
Ohyagi, Y., Asahara, H., Chui, D.-H., Tsuruta, Y., Sakae, N., Miyoshi, K., Yamada, T., Kikuchi, H., Taniwaki, T., Murai, H., et al. (2005) · The FASEB Journal · doi:10.1096/fj.04-2637fje · Cited by 281
Karran, E. H., & Hardy, J. (2014) · Annals of Neurology · doi:10.1002/ana.24188 · Cited by 279
Brambilla, R., Persaud, T., Hu, X., Karmally, S., Shestopalov, V. I., Dvoriantchikova, G., Ivanov, D., Nathanson, L., Barnum, S. R., & Bethea, J. R. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0802954 · Cited by 279
Cerebrospinal fluid neurogranin: relation to cognition and neurodegeneration in Alzheimer’s disease
Portelius, E., Zetterberg, H., Skillbäck, T., Törnqvist, U., Andreasson, U., Trojanowski, J. Q., Weiner, M. W., Shaw, L. M., & Mattsson, N. (2015) · Brain · doi:10.1093/brain/awv267 · Cited by 279 · cited 1×
“Several studies have revealed an elevation of CSF neurogranin in AD and MCI individuals compared to healthy controls.(547,548) The CSF neurogranin levels correlated with the brain amyloid load in patients with preclinical AD.”
ResultEndogenous amyloid‐β is necessary for hippocampal synaptic plasticity and memory
Puzzo, D., Privitera, L., Fa', M., Staniszewski, A., Hashimoto, G., Aziz, F., Sakurai, M., Ribe, E. M., Troy, C. M., Mercken, M., et al. (2011) · Annals of Neurology · doi:10.1002/ana.22313 · Cited by 278
alpha-Bungarotoxin-sensitive hippocampal nicotinic receptor channel has a high calcium permeability
Castro, N. G., & Albuquerque, E. X. (1995) · Biophysical Journal · doi:10.1016/s0006-3495(95)80213-4 · Cited by 273 · cited 2×
“Among the isofroms, the α7-nAChRs had the highest Ca permeability.(381) The mechanism behind Aβ-induced α7-nAChR activation could be due to the disruption of intracellular signal transduction to stimulate the calcium influx.”
BackgroundMondragón-Rodríguez, S., Trillaud-Doppia, E., Dudilot, A., Bourgeois, C., Lauzon, M., Leclerc, N., & Boehm, J. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.401240 · Cited by 272 · cited 2×
“Missorted tau proteins at postsynaptic terminals interacts with the subunits of AMPARs and NMDARs, leading to the excessive activation of glutamate receptors, Ca influx, impaired LTP and enhanced LTD.(92,100,101) It has been demonstrated that the absence of tau proteins prevent Aβ-induced LTP impairment mouse hippocam…”
BackgroundDurairajan, S. S. K., Liu, L.-F., Lu, J.-H., Chen, L.-L., Yuan, Q., Chung, S. K., Huang, L., Li, X.-S., Huang, J.-D., & Li, M. (2012) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2012.02.016 · Cited by 271
Chen, X., Johnson, V. E., Uryu, K., Trojanowski, J. Q., & Smith, D. H. (2009) · Brain Pathology · doi:10.1111/j.1750-3639.2008.00176.x · Cited by 267
Direct Activation of Bax Protein for Cancer Therapy
Liu, Z., Ding, Y., Ye, N., Wild, C., Chen, H., & Zhou, J. (2015) · Medicinal Research Reviews · doi:10.1002/med.21379 · Cited by 260 · cited 1×
“416 In contrast, Aβ42 stimulated the expression of Bax, which induced cell apoptosis and was commonly observed in many cancers.(416,417)”
BackgroundSelf-citationNeurovascular Dysfunction and Faulty Amyloid -Peptide Clearance in Alzheimer Disease
Sagare, A. P., Bell, R. D., & Zlokovic, B. V. (2012) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a011452 · Cited by 251
Iwatsubo, T., Saido, T. C., Mann, D. M. A., Lee, V. M.-Y., & Trojanowski, J. Q. (1996) · Europe PMC (PubMed Central) · Cited by 248
Saito, T., Mihira, N., Matsuba, Y., Sasaguri, H., Hashimoto, S., Narasimhan, S., Zhang, B., Murayama, S., Higuchi, M., Lee, V. M. Y., et al. (2019) · Journal of Biological Chemistry · doi:10.1074/jbc.ra119.009487 · Cited by 248
Neurogranin as a Cerebrospinal Fluid Biomarker for Synaptic Loss in Symptomatic Alzheimer Disease
Kester, M. I., Teunissen, C. E., Crimmins, D. L., Herries, E. M., Ladenson, J. H., Scheltens, P., van der Flier, W. M., Morris, J. C., Holtzman, D. M., & Fagan, A. M. (2015) · JAMA Neurology · doi:10.1001/jamaneurol.2015.1867 · Cited by 246 · cited 1×
“Several studies have revealed an elevation of CSF neurogranin in AD and MCI individuals compared to healthy controls.(547,548) The CSF neurogranin levels correlated with the brain amyloid load in patients with preclinical AD.”
ResultApproval of Aducanumab for Alzheimer Disease—The FDA’s Perspective
Dunn, B., Stein, P., & Cavazzoni, P. (2021) · JAMA Internal Medicine · doi:10.1001/jamainternmed.2021.4607 · Cited by 246 · cited 3×
“In June 2021, aducanumab was approved by the FDA for medical use.(47,48) However, it is considered controversial due to the lack of sufficient evidence to support its efficacy.”
BackgroundMethodPapouin, T., Dunphy, J. M., Tolman, M., Dineley, K. T., & Haydon, P. G. (2017) · Neuron · doi:10.1016/j.neuron.2017.04.021 · Cited by 243 · cited 1×
“In the CNS, the nicotinic acetylcholine receptors (nAChRs) are expressed in both neurons and non-neuronal cells.(379,380) As ligand-gated ion channels, nAChRs opened in response to the depolarization of the membrane, allowing Na, K and Ca to enter the cells.”
Backgroundβ-Amyloid Peptide Activates α7 Nicotinic Acetylcholine Receptors Expressed in Xenopus Oocytes
Dineley, K. T., Bell, K. A., Bui, D., & Sweatt, J. D. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m200066200 · Cited by 242
Bartlett, J. A., Fath, M. J., DeMasi, R. A., Hermes, A., Quinn, J., Mondou, E., & Rousseau, F. S. (2006) · AIDS · doi:10.1097/01.aids.0000247578.08449.ff · Cited by 242 · cited 2×
“Accordingly, combination therapy should be considered for the clinical phase of the disease, which is already the standard of care for many diseases, including rheumatoid arthritis and HIV/AIDS.479,480 Growing evidence indicates that Aβ accumulation stimulates tau phosphorylation and fibrillary tangle formation, leadi…”
BackgroundNeurogenic Effect of -Amyloid Peptide in the Development of Neural Stem Cells
Lopez-Toledano, M. A. (2004) · Journal of Neuroscience · doi:10.1523/jneurosci.0974-04.2004 · Cited by 241
Targeting Prodromal Alzheimer Disease With Avagacestat: A Randomized Clinical Trial
Coric, V., Salloway, S., van Dyck, C. H., Dubois, B., Andreasen, N., Brody, M., Curtis, C., Soininen, H., Thein, S., Shiovitz, T., et al. (2015) · JAMA Neurology · doi:10.1001/jamaneurol.2015.0607 · Cited by 240 · cited 1×
“However, it was terminated in Phase 2 trials due to gastrointestinal and dermatological side effects.(315) These failures popularized the development of γ-secretase modulators (GSMs) as an alternative approach.”
BackgroundAlexander, G. C., Emerson, S., & Kesselheim, A. S. (2021) · JAMA · doi:10.1001/jama.2021.3854 · Cited by 240 · cited 3×
“In June 2021, aducanumab was approved by the FDA for medical use.(47,48) However, it is considered controversial due to the lack of sufficient evidence to support its efficacy.”
BackgroundMethodMitochondrial Protein Synthesis, Import, and Assembly
Fox, T. D. (2012) · Genetics · doi:10.1534/genetics.112.141267 · Cited by 237 · cited 1×
“Instead, most proteins of the mitochondria are synthesized by cytosolic ribosomes then imported into the organelle.(202) APP- or Aβ-induced impairment of mitochondrial import pathway has been considered as a hallmark of AD.”
BackgroundCSF biomarkers for Alzheimer disease correlate with cortical brain biopsy findings
Seppälä, T. T., Nerg, O., Koivisto, A. M., Rummukainen, J., Puli, L., Zetterberg, H., Pyykkö, O. T., Helisalmi, S., Alafuzoff, I., Hiltunen, M., et al. (2012) · Neurology · doi:10.1212/wnl.0b013e3182563bd0 · Cited by 236
Pera, M., Larrea, D., Guardia‐Laguarta, C., Montesinos, J., VELASCO, K. R., Agrawal, R. R., Xu, Y., Chan, R., Paolo, G. D., Mehler, M. F., et al. (2017) · The EMBO Journal · doi:10.15252/embj.201796797 · Cited by 236 · cited 1×
“C99, a C-terminal fragment of APP cleaved by β-secretase, also activated sphingolipid turnover and increased ceramide to impact the ERmitochondria contacts, leading to impaired mitochondrial respiration and metabolic disturbance.(212) Mitochondria are also the major source of oxidative stress because the inevitable le…”
BackgroundBrown, B. M., Peiffer, J. J., Taddei, K., Lui, J. K., Laws, S. M., Gupta, V. B., Taddei, T., Ward, V. K., Rodrigues, M. A., Burnham, S., et al. (2013) · Molecular Psychiatry · doi:10.1038/mp.2012.107 · Cited by 235
A key role for MAM in mediating mitochondrial dysfunction in Alzheimer disease
Area-Gomez, E., de Groof, A., Bonilla, E., Montesinos, J., Tanji, K., Boldogh, I., Pon, L., & Schon, E. A. (2018) · Cell Death & Disease · doi:10.1038/s41419-017-0215-0 · Cited by 235 · cited 1×
“Alteration of mitochondria-associated endoplasmic reticulum membrane (MAM) signaling has been implicated in neurodegenerative diseases such as AD.(208,209) Overexpression of APP mutants or Aβ aggregates increased ER-mitochondria connectivity, resulting in the elevation of mitochondrial calcium.”
BackgroundAshrafi, G., de Juan‐Sanz, J., Farrell, R. J., & Ryan, T. A. (2019) · Neuron · doi:10.1016/j.neuron.2019.11.020 · Cited by 235
Failure of Neuronal Maturation in Alzheimer Disease Dentate Gyrus
Li, B., Yamamori, H., Tatebayashi, Y., Shafit-Zagardo, B., Tanimukai, H., Chen, S., Iqbal, K., & Grundke-Iqbal, I. (2008) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0b013e318160c5db · Cited by 234 · cited 1×
“It has been demonstrated that the expression of microtubule-associated protein (MAP) isoforms MAP2a, a marker of the mature neuron, was dramatically decreased in the dentate gyrus of human AD brains, indicating a reduction of neuronal maturation in the hippocampus.(429) Another study also found a reduced number of DCX…”
ResultBaik, S. H., Kang, S., Son, S. M., & Mook-Jung, I. (2016) · Glia · doi:10.1002/glia.23074 · Cited by 234
Evaluating the Safety and Efficacy of Crenezumab vs Placebo in Adults With Early Alzheimer Disease
Ostrowitzki, S., Bittner, T., Sink, K. M., Mackey, H. M., Rabe, C., Honig, L. S., Cassetta, E., Woodward, M., Boada, M., van Dyck, C. H., et al. (2022) · JAMA Neurology · doi:10.1001/jamaneurol.2022.2909 · Cited by 234
Disruption of fast axonal transport is a pathogenic mechanism for intraneuronal amyloid beta
Pigino, G. F., Morfini, G. A., Atagi, Y., Deshpande, A., Yu, C., Jungbauer, L. M., LaDu, M. J., Busciglio, J. A., & Brady, S. T. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0901229106 · Cited by 233 · cited 1×
“Recently, two parallel studies have further investigated the underlying mechanism of the Aβ’s detrimental effect over synaptic transmission.(87,88) They found that intracellular administration of the AβOs rather than administration of the AβOs at the extracellular level altered the synaptic transmission and fast axona…”
BackgroundBlood-derived amyloid-β protein induces Alzheimer’s disease pathologies
Bu, X., Xiang, Y., Jin, W.-S., Wang, J., Shen, L.-L., Huang, Z.-L., Zhang, K., Liu, Y.-H., Zeng, F., Liu, H., et al. (2017) · Molecular Psychiatry · doi:10.1038/mp.2017.204 · Cited by 233
Self-citationvan Lengerich, B., Zhan, L., Xia, D., Chan, D., Joy, D., Park, J. I., Tatarakis, D., Calvert, M., Hummel, S., Lianoglou, S., et al. (2023) · Nature Neuroscience · doi:10.1038/s41593-022-01240-0 · Cited by 233
Increased CSF neurogranin concentration is specific to Alzheimer disease
Wellington, H., Paterson, R. W., Portelius, E., Törnqvist, U., Magdalinou, N., Fox, N. C., Blennow, K., Schott, J. M., & Zetterberg, H. (2016) · Neurology · doi:10.1212/wnl.0000000000002423 · Cited by 232 · cited 1×
“More importantly, the CSF neurogranin increases exclusively in AD patients and has not been observed in other neurodegenerative disorders, such as frontotemporal dementia or Parkinson’s disease.(550) MicroRNA (miRNA) are noncoding RNA molecules of 20–25 nucleotides that can manipulate gene expression posttranscription…”
BackgroundImmune reactive cells in senile plaques and cognitive decline in Alzheimer’s disease
Vehmas, A. K., Kawas, C. H., Stewart, W. F., & Troncoso, J. C. (2003) · Neurobiology of Aging · doi:10.1016/s0197-4580(02)00090-8 · Cited by 230 · cited 1×
“The reactive astrocytes are close to Aβ plaques in brains from AD patients and rodent models.(183,184) Astrocytes response to Aβ aggregates in a TLR-dependent manner, which further activates the target genes to produce proinflammatory factors.”
BackgroundAMPA receptor downscaling at the onset of Alzheimer's disease pathology in double knockin mice
Chang, E. H., Savage, M. J., Flood, D. G., Thomas, J. M., Levy, R. B., Mahadomrongkul, V., Shirao, T., Aoki, C., & Huerta, P. T. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0507313103 · Cited by 225 · cited 1×
“It has been identified that APP overexpression and increase of soluble Aβ oligomers are related with the downregulation of GluA1/2 subunits of AMPARs, leading to the inhibition of synaptic plasticity, spine loss, and memory deficits.(231,232) The basal forebrain cholinergic system is one of the earliest brain regions…”
BackgroundHe, X., Qin, W., Liu, Y., Zhang, X., Duan, Y., Song, J., Li, K., Jiang, T., & Yu, C. (2013) · Human Brain Mapping · doi:10.1002/hbm.22414 · Cited by 224
Drachman, D. A. (2014) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2013.11.003 · Cited by 224
The role of the immune system in Alzheimer disease: Etiology and treatment
Jevtic, S. D., Sengar, A. S., Salter, M. W., & McLaurin, J. (2017) · Ageing Research Reviews · doi:10.1016/j.arr.2017.08.005 · Cited by 224 · cited 1×
“The immune system has long been implicated as an important factor in Alzheimer’s development.(474) However, murine immune system is notably different from humans.”
BackgroundRowe, C. C., Bourgeat, P., Ellis, K. A., Brown, B., Lim, Y. Y., Mulligan, R., Jones, G., Maruff, P., Woodward, M., Price, R., et al. (2013) · Annals of Neurology · doi:10.1002/ana.24040 · Cited by 222
Crews, L., Adame, A., Patrick, C., DeLaney, A., Pham, E., Rockenstein, E., Hansen, L., & Masliah, E. (2010) · The Journal of Neuroscience · doi:10.1523/jneurosci.1305-10.2010 · Cited by 222 · cited 1×
“Another study also found a reduced number of DCX- and Sox2-positive cells in the AD hippocampus as compared with non-demented controls.(430) Furthermore, a study including 45 Alzheimer’s patients between 52 and 97 years of age identified that the number of DCX-positive cells declined with the neuropathological progres…”
ResultMagdesian, M. H., Carvalho, M. M. V. F., Mendes, F. A., Saraiva, L. M., Juliano, M. A., Juliano, L., Garcia-Abreu, J., & Ferreira, S. T. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m707108200 · Cited by 221
Gene–environment interactions in Alzheimer disease: the emerging role of epigenetics
Migliore, L., & Coppedè, F. (2022) · Nature Reviews Neurology · doi:10.1038/s41582-022-00714-w · Cited by 217
Ding, B., Lin, C., Liu, Q., He, Y., Ruganzu, J. B., Jin, H., Peng, X., Ji, S., Ma, Y., & Yang, W. (2020) · Journal of Neuroinflammation · doi:10.1186/s12974-020-01981-4 · Cited by 215
Frenkel, D., Wilkinson, K., Zhao, L., Hickman, S. E., Means, T. K., Puckett, L., Farfara, D., Kingery, N. D., Weiner, H. L., & El Khoury, J. (2013) · Nature Communications · doi:10.1038/ncomms3030 · Cited by 214
β-Amyloid Regulation of Presynaptic Nicotinic Receptors in Rat Hippocampus and Neocortex
Dougherty, J. J., Wu, J., & Nichols, R. A. (2003) · Journal of Neuroscience · doi:10.1523/jneurosci.23-17-06740.2003 · Cited by 213
Hong, S., Ostaszewski, B. L., Yang, T., O’Malley, T. T., Jin, M., Yanagisawa, K., Li, S., Bartels, T., & Selkoe, D. J. (2014) · Neuron · doi:10.1016/j.neuron.2014.02.027 · Cited by 213 · cited 1×
“For example, AβOs bind to sialic acid-containing GM1 ganglioside on cell membrane to induce LTP impairment.(64) On the other hand, cholesterol-rich lipid rafts provide an optimal environment for Aβ synthesis and enhance the interaction of Aβ with the membrane.”
Klein, G., Delmar, P., Voyle, N., Rehal, S., Hofmann, C., Abi-Saab, D., Andjelkovic, M., Ristic, S., Wang, G., Bateman, R., et al. (2019) · Alzheimer's Research & Therapy · doi:10.1186/s13195-019-0559-z · Cited by 212 · cited 1×
“The antibody was found to be safe and well tolerated during the Phase 1 clinical trials, except that transient amyloid-related imaging abnormalities (ARIA) appeared in some patients given a high dosage.(336) The initial results of phase 2 studies suggested gantenerumab may have no efficacy in the enrolled cohort.”
BackgroundMitochondrial Dysfunction and Synaptic Transmission Failure in Alzheimer’s Disease
Guo, L., Tian, J., & Du, H. (2017) · Journal of Alzheimer’s Disease · doi:10.3233/jad-160702 · Cited by 211 · cited 1×
“Mitochondria are essential for the glutamate synthesis, synaptic transmission and calcium regulation.(193,194) Disrupted energy metabolism has been found in early AD and precedes the disease development, suggesting the core role of mitochondria dysfunction in Alzheimer’s pathogenesis.”
BackgroundBourgade, K., Garneau, H., Giroux, G., Le Page, A. Y., Bocti, C., Dupuis, G., Frost, E. H., & Fülöp, T. (2015) · Biogerontology · doi:10.1007/s10522-014-9538-8 · Cited by 208
May, P. C., Willis, B. A., Lowe, S. L., Dean, R. A., Monk, S. A., Cocke, P. J., Audia, J. E., Boggs, L. N., Borders, A. R., Brier, R. A., et al. (2015) · The Journal of Neuroscience · doi:10.1523/jneurosci.4129-14.2015 · Cited by 206 · cited 1×
“LY2886721 was the first BACE inhibitor to reach Phase 2 clinical trials.(304) Compared to the previous compound, it has better brain penetrance.”
BackgroundPeripheral inflammatory biomarkers in Alzheimer’s disease: a brief review
Park, J., Han, S.-H., & Mook‐Jung, I. (2020) · BMB Reports · doi:10.5483/bmbrep.2020.53.1.309 · Cited by 206
Early detection of cognitive deficits in the 3xTg-AD mouse model of Alzheimer's disease
Stover, K. R., Campbell, M. A., Winssen, C. M. V., & Brown, R. E. (2015) · Behavioural Brain Research · doi:10.1016/j.bbr.2015.04.012 · Cited by 203
Systematic Regional Variations in the Loss of Cortical Cholinergic Fibers in Alzheimer's Disease
Geula, C., & Mesulam, M.-M. (1996) · Cerebral Cortex · doi:10.1093/cercor/6.2.165 · Cited by 202 · cited 1×
“The basal forebrain cholinergic system is one of the earliest brain regions vulnerable to degeneration during AD.(233) The correlations between enhanced BACE1 activity, Aβ accumulation with atrophy of basal forebrain and loss of functional connectivity have been found in neuropathological and neuroimaging studies.”
BackgroundXia, X., Wang, Y., Huang, Y., Zhang, H., Lu, H., & Zheng, J. C. (2019) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2019.101694 · Cited by 202 · cited 1×
“Therefore, they become an attractive target for developing AD biomarkers.(551,552) In addition to body fluids, ocular markers also gain increasing interest.”
BackgroundJack, C. R., Wiste, H. J., Botha, H., Weigand, S. D., Therneau, T. M., Knopman, D. S., Graff-Radford, J., Jones, D. T., Ferman, T. J., Boeve, B. F., et al. (2019) · Brain · doi:10.1093/brain/awz268 · Cited by 200 · cited 1×
“In the clinical setting, neuroimaging of sporadic Alzheimer’s patients show the increased cortical tau-PET ligand retention only in the presence of Aβ accumulation, which is also associated with cortical atrophy in AD.(110) In addition, longitudinal studies idenfied that antecedent Aβ aggregates could successfully pre…”
BackgroundIron(II) Binding to Amyloid-β, the Alzheimer’s Peptide
Garah, F. E., Bijani, C., Coppel, Y., Faller, P., & Hureau, C. (2011) · Inorganic Chemistry · doi:10.1021/ic201233b · Cited by 199
Involvement of aberrant glycosylation in phosphorylation of tau by cdk5 and GSK‐3β
Liu, F., Iqbal, K., Grundke, I., & Gong, C. (2002) · FEBS Letters · doi:10.1016/s0014-5793(02)03487-7 · Cited by 197 · cited 2×
“CDK5-P25 phosphorylates tau at sites of Thr181, Ser199, Ser202, Thr205, Thr212, Ser214, Ser217, Thr231, Ser235, Ser396, and Ser404.(121) Thus, inhibitors of GSK-3β or CDK-5 such as AZD1080 and roscovitine, markedly reduced the levels of tau phosphorylation and prevented further tau aggregation.”
BackgroundSudweeks, S. N., & Yakel, J. L. (2000) · The Journal of Physiology · doi:10.1111/j.1469-7793.2000.00515.x · Cited by 197 · cited 1×
“In the CNS, the nicotinic acetylcholine receptors (nAChRs) are expressed in both neurons and non-neuronal cells.(379,380) As ligand-gated ion channels, nAChRs opened in response to the depolarization of the membrane, allowing Na, K and Ca to enter the cells.”
BackgroundGuo, Q., Sebastian, L., Sopher, B. L., Miller, M. W., Ware, C. B., Martin, G. M., & Mattson, M. P. (1999) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1999.0721019.x · Cited by 197 · cited 1×
“Conversely, application of Aβ to primary hippocampal neurons from PSEN1 mutant knock-in mice significantly increased superoxide production.(423) Physiological amounts (picomolar concentrations) of Aβ peptides could function as anti-oxidants by inhibiting redox metals, such as Cu, Fe and Zn to bind with ligands in redo…”
BackgroundCheng, Y., Tian, D., & Wang, Y.-J. (2020) · Translational Neurodegeneration · doi:10.1186/s40035-020-00195-1 · Cited by 197
Traditional C hinese medicine and cancer: History, present situation, and development
Liu, J., Wang, S., Zhang, Y., et al. (2015) · Thoracic Cancer · doi:10.1111/1759-7714.12270 · Cited by 196
Self-citationEckman, E. A., Adams, S. K., Troendle, F. J., Stodola, B. A., Kahn, M. A., Fauq, A. H., Xiao, H. D., Bernstein, K. E., & Eckman, C. B. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m605827200 · Cited by 196 · cited 1×
“degrading enzyme (IDE), matrix metalloproteinase (MMPs), angiotensin converting enzyme (ACE), and endothelinconverting enzyme (ECE), serine proteases, cystein proteases, and kallikrein-related peptidase 7.(30,31) In the hippocampus of AD patients, the enzymes IDE, ACE and NEP had decreased activity.”
BackgroundWhite, M. R., Kandel, R., Tripathi, S., Condon, D., Qi, L., Taubenberger, J., & Hartshorn, K. L. (2014) · PLoS ONE · doi:10.1371/journal.pone.0101364 · Cited by 193 · cited 1×
“Aβ stimulated the aggregation of viral particles, which facilitated leukocyte-mediated uptake of viruses.(405) In addition, the damaged host cells released nucleic acids containing Aβ aggregates, which were immunogenic and elicited the secretion of type I interferons (IFNs) by adjacent microglia to accomplish the anti…”
BackgroundCummings, J. L., Zhong, K., Kinney, J. W., Heaney, C., Moll-Tudla, J., Joshi, A., Pontecorvo, M., Devous, M., Tang, A., & Bena, J. (2016) · Alzheimer's Research & Therapy · doi:10.1186/s13195-016-0173-2 · Cited by 190
Caspase-2 cleavage of tau reversibly impairs memory
Zhao, X., Kotilinek, L. A., Smith, B., Hlynialuk, C., Zahs, K., Ramsden, M., Cleary, J., & Ashe, K. H. (2016) · Nature Medicine · doi:10.1038/nm.4199 · Cited by 187 · cited 2×
“Missorted tau proteins at postsynaptic terminals interacts with the subunits of AMPARs and NMDARs, leading to the excessive activation of glutamate receptors, Ca influx, impaired LTP and enhanced LTD.(92,100,101) It has been demonstrated that the absence of tau proteins prevent Aβ-induced LTP impairment mouse hippocam…”
BackgroundAmyloid beta mediates memory formationPreprint
García‐Osta, A., & Alberini, C. M. (2009) · Learning & Memory · doi:10.1101/lm.1310209 · Cited by 185
Three Histidine Residues of Amyloid-β Peptide Control the Redox Activity of Copper and Iron
Nakamura, M., Shishido, N., Nunomura, A., Smith, M. A., Perry, G. L., Hayashi, Y., Nakayama, K., & Hayashi, T. (2007) · Biochemistry · doi:10.1021/bi701079z · Cited by 184
Successful therapies for Alzheimer’s disease: why so many in animal models and none in humans?
Franco, R., & Cedazo-Minguez, A. (2014) · Frontiers in Pharmacology · doi:10.3389/fphar.2014.00146 · Cited by 183 · cited 1×
“Furthermore, the extensive neuronal loss in AD patients has not been replicated in the murine models.(476) Thus, a lack of accurate disease models leads to a translational gap between animal research and the clinical setting.”
BackgroundAmyloid-β Peptides are Generated in Mitochondria-Associated Endoplasmic Reticulum Membranes
Schreiner, B., Hedskog, L., Wiehager, B., & Ankarcrona, M. (2014) · Journal of Alzheimer s Disease · doi:10.3233/jad-132543 · Cited by 180
Amyloid-β is an antioxidant for lipoproteins in cerebrospinal fluid and plasma
Kontush, A., Berndt, C., Weber, W., Akopyan, V., Arlt, S., Schippling, S., & Beisiegel, U. (2001) · Free Radical Biology and Medicine · doi:10.1016/s0891-5849(00)00458-5 · Cited by 180
Pickett, E. K., Herrmann, A. G., McQueen, J., Abt, K., Dando, O., Tulloch, J., Jain, P., Dunnett, S., Sohrabi, S., Fjeldstad, M. P., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.11.044 · Cited by 179 · cited 1×
“As the upstream factor, Aβ triggered the hyperphosphorylation of tau protiens, which synergistically induced neuronal impairment and cognitive deficits.(111,115) Aβ accelerated the tau hyperphosphorylation by the activation of cyclindependent kinase 5 (CDK5) and glycogen synthase kinase 3 (GSK-3).”
BackgroundNilson, A. N., English, K. C., Gerson, J. E., Whittle, T. B., Crain, C. N., Xue, J. J., Sengupta, U., Castillo‐Carranza, D. L., Zhang, W., Gupta, P. K., et al. (2016) · Journal of Alzheimer s Disease · doi:10.3233/jad-160912 · Cited by 178 · cited 1×
“Tau oligomers not only led to neuronal damage but also bound to astrocytes and microglia to induce neuroinflammation.(136) In hippocampal neurons, Aβ also induced the activation of calpain-1 and generated a 17-kDa tau fragment, resulting in neurite degeneration and neuronal death.”
BackgroundAshok, A., Rai, N. K., Tripathi, S., & Bandyopadhyay, S. (2015) · Toxicological Sciences · doi:10.1093/toxsci/kfu208 · Cited by 177
The BACE‐1 inhibitor CNP520 for prevention trials in Alzheimer's disease
Neumann, U., Ufer, M., Jacobson, L. H., Rouzade‐Dominguez, M., Huledal, G., Kolly, C., Lüönd, R. M., Machauer, R., Veenstra, S. J., Hurth, K., et al. (2018) · EMBO Molecular Medicine · doi:10.15252/emmm.201809316 · Cited by 177 · cited 1×
“Besides LY2886721, many other candidates have also reached late stages of clinical trials, including atabecestat (Phase 2/3),(305) elenbecestat (Phase 3),(306) lanabecestat (Phase 2/ 3)(307,308) and umibecestat (Phase 2/3).(309) However, all of them have failed to receive final approval to reach the market.”
BackgroundAAVrh.10-Mediated APOE2 Central Nervous System Gene Therapy for APOE4-Associated Alzheimer's Disease
Rosenberg, J. B., Kaplitt, M. G., De, B. P., Chen, A., Flagiello, T., Salami, C., Pey, E., Zhao, L., Ricart Arbona, R. J., Monette, S., et al. (2018) · Human Gene Therapy Clinical Development · doi:10.1089/humc.2017.231 · Cited by 176
Presenilin-Dependent -Secretase-Mediated Control of p53-Associated Cell Death in Alzheimer's Disease
Alves da Costa, C., Sunyach, C., Pardossi-Piquard, R., Sevalle, J., Vincent, B., Boyer, N., Kawarai, T., Girardot, N., St. George-Hyslop, P., & Checler, F. (2006) · Journal of Neuroscience · doi:10.1523/jneurosci.0651-06.2006 · Cited by 168
Clearance of Amyloid-β Peptides By Microglia and Macrophages: the Issue of What, When and Where
Lai, A. Y., & McLaurin, J. (2012) · Future Neurology · doi:10.2217/fnl.12.6 · Cited by 166 · cited 1×
“To compensate the impaired clearance of Aβ, peripheral macrophages are recruited to the brain in an effort to clear Aβ plaques, which likely worsens the sustained inflammation and thus AD pathologies.(172,173) Compared with microglia distal to the amyloid in AD brain tissues, there is an increased expression of TREM2…”
BackgroundBode, D. C., Freeley, M., Nield, J., Palma, M., & Viles, J. H. (2019) · Journal of Biological Chemistry · doi:10.1074/jbc.ac118.007195 · Cited by 166
Lahmy, V., Meunier, J., Malmström, S., Naert, G., Givalois, L., Kim, S. H., Villard, V., Vamvakides, A., & Maurice, T. (2013) · Neuropsychopharmacology · doi:10.1038/npp.2013.70 · Cited by 165 · cited 1×
“ANAVEX®2-73 (Blarcamesine), which targets sigma-1 and M1 muscarinic receptors, has also demonstrated its diseasemodifying activity in AD transgenic mice (3xTg-AD), including reducing amyloid and tau pathologies as well as improving cognitive deficits.(51,52) The results of its Phase 2B/3 study, presented at the Clinic…”
BackgroundSun, X., He, G., & Song, W. (2006) · The FASEB Journal · doi:10.1096/fj.05-5632com · Cited by 163
Self-citationTargeting Fyn Kinase in Alzheimer’s Disease
Nygaard, H. B. (2018) · Biological Psychiatry · doi:10.1016/j.biopsych.2017.06.004 · Cited by 162 · cited 1×
“Accordingly, inhibition of Fyn improved the cognitive deficits in transgenic mice with Aβ and tau depositions.(144,145) PET and CSF tests also indicate the synergy between Aβ and tau, which leads to brain dysfunction and cognitive impairment.”
BackgroundThe synapse as a treatment avenue for Alzheimer’s Disease
Peng, L., Bestard‐Lorigados, I., & Song, W. (2022) · Molecular Psychiatry · doi:10.1038/s41380-022-01565-z · Cited by 162 · cited 1×
“Targeting synapse loss and dysfunction may be an effective AD treatment strategy.(489) Once the pathological cascade has begun, combination therapy targeting multiple AD pathologies will be more effective than a single therapy, which only addresses one abnormal factor.”
BackgroundSelf-citationProstaglandin signaling suppresses beneficial microglial function in Alzheimer’s disease models
Johansson, J. U., Woodling, N. S., Wang, Q., Panchal, M., Liang, X., Trueba-Saiz, A., Brown, H. D., Mhatre, S. D., Loui, T., & Andreasson, K. I. (2015) · Journal of Clinical Investigation · doi:10.1172/jci77487 · Cited by 161
Leroy, K., Ando, K., Laporte, V., Dedecker, R., Suain, V., Authelet, M., Héraud, C., Pierrot, N., Yilmaz, Z., Octave, J.-N., et al. (2012) · The American Journal of Pathology · doi:10.1016/j.ajpath.2012.08.012 · Cited by 161 · cited 1×
“Thus, knocking out the tau genes in the APP/PS1 mice inhibited the amyloidogenic pathway of APP processing, Aβ production and the amyloid plaque formation.(138) Furthermore, the neurotoxicity of Aβ is tau-dependent.”
BackgroundBourgade, K., Le Page, A., Bocti, C., Witkowski, J. M., Dupuis, G., Frost, E. H., & Fülöp, T. (2016) · Journal of Alzheimer’s Disease · doi:10.3233/jad-150652 · Cited by 161 · cited 1×
“It is hypothesized that the anti-microbial activity of Aβ is associated with its capacity to bind with microorganisms and form a net to trap the infectious agents.(399) This idea fits with the findings that HSV1 and Borrelia DNA have been found in plaque cores of AD brains.”
ResultThe role of microglial cells and astrocytes in fibrillar plaque evolution in transgenic APPSW mice
Wegiel, J. (2001) · Neurobiology of Aging · doi:10.1016/s0197-4580(00)00181-0 · Cited by 159 · cited 1×
“Impaired astrocyte activity also increased the number of microglia surrounding Aβ plaques and altered the microglia status.(189) In turn, microglia could alter the status of astrocytes.”
BackgroundIncreased MAP kinase activity in Alzheimer's and Down syndrome but not in schizophrenia human brain
SWATTON, J. E., Sellers, L. A., Faull, R. L. M., Holland, A. J., Iritani, S., & Bahn, S. (2004) · European Journal of Neuroscience · doi:10.1111/j.0953-816x.2004.03365.x · Cited by 158 · cited 1×
“Further studies have found that mitogen-activated protein kinases (MAPKs) including ERK1/2, SAPKs and p38 are also involved in Aβ-induced formation of PHF-tau during AD.(124,125) Cellular prion protein (PrPC) has been found as a receptor for toxic Aβ oligomers to induce LTP loss and cognitive impairment in AD model mi…”
BackgroundAmyloid pathology and axonal injury after brain trauma
Scott, G., Ramlackhansingh, A. F., Edison, P., Hellyer, P. J., Cole, J. H., Veronese, M., Leech, R., Greenwood, R., Turkheimer, F., Gentleman, S., et al. (2016) · Neurology · doi:10.1212/wnl.0000000000002413 · Cited by 157
Wolk, D. A. (2011) · Archives of Neurology · doi:10.1001/archneurol.2011.153 · Cited by 156
Liu, C., Song, X., Nisbet, R. M., & Götz, J. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.641902 · Cited by 156
Animal models of Alzheimer’s disease: Applications, evaluation, and perspectives
Chen, Z.-Y., 北京大学生命科学学院膜生物学国家重点实验室, 北. 1., State Key Laboratory of Membrane Biology, C. O. L. S., & Zhang, Y. (2022) · Zoological Research · doi:10.24272/j.issn.2095-8137.2022.289 · Cited by 155 · cited 1×
“In order to study Alzheimer’s pathogenesis and therapeutic strategies, better animal models to recapitulate the natural process of the disease are required.(443,444) Many transgenic mouse models have been developed and commonly used, including the mice containing mutations in the APP (e.”
BackgroundSelf-citationOcular changes in TgF344-AD rat model of Alzheimer's disease
Tsai, Y., Lu, B., Ljubimov, A. V., Girman, S., Ross-Cisneros, F. N., Sadun, A. A., Svendsen, C. N., Cohen, R. M., & Wang, S. (2014) · Investigative Opthalmology & Visual Science · doi:10.1167/iovs.13-12888 · Cited by 153
Unwin, N. (2013) · Quarterly Reviews of Biophysics · doi:10.1017/s0033583513000061 · Cited by 153 · cited 1×
“As ligand-gated ion channels, nAChRs opened in response to the depolarization of the membrane, allowing Na, K and Ca to enter the cells.(381,382) Among the isofroms, the α7-nAChRs had the highest Ca permeability.”
BackgroundThe Role of Biomarkers in Alzheimer’s Disease Drug Development
Cummings, J. L. (2019) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-05542-4_2 · Cited by 153 · cited 1×
“Identification of early Alzheimer’s biomarkers Biomarkers that can identify patients at very early stages of AD will greatly benefit the development of disease-modifying therapies.(539) In addition to the typical pathologies (e.”
BackgroundGrothe, M. J., Teipel, S. J., & Initiative, F. T. A. D. N. (2016) · Human Brain Mapping · doi:10.1002/hbm.23018 · Cited by 150
Inhibition of Angiogenesis by Aβ Peptides
Paris, D., Townsend, K., Quadros, A., Humphrey, J., Sun, J., Brem, S., Wotoczek-Obadia, M., DelleDonne, A., Patel, N., Obregon, D. F., et al. (2004) · Angiogenesis · doi:10.1023/b:agen.0000037335.17717.bf · Cited by 148
Abnormal Cognition, Sleep, EEG and Brain Metabolism in a Novel Knock-In Alzheimer Mouse, PLB1
Platt, B., Drever, B. D., Koss, D. J., Stoppelkamp, S., Jyoti, A., Plano, A., Utan, A., Merrick, G., Ryan, D., Melis, V., et al. (2011) · PLoS ONE · doi:10.1371/journal.pone.0027068 · Cited by 147
Tai, H., Wang, B. Y., Serrano‐Pozo, A., Frosch, M. P., Spires‐Jones, T. L., & Hyman, B. T. (2014) · Acta Neuropathologica Communications · doi:10.1186/s40478-014-0146-2 · Cited by 147 · cited 1×
“AβOs induce tau hyperphosphorylation and accumulation in dendritic spine, which further lead to synaptic loss and dysfunction.(94,95) The level of pathological tau in AD patients is correlated with the severity of impaired synaptic plasticity and cognitive dysfunction.”
BackgroundFunctional network integrity presages cognitive decline in preclinical Alzheimer disease
Buckley, R. F., Schultz, A. P., Hedden, T., Papp, K. V., Hanseeuw, B. J., Marshall, G. A., Sepulcre, J., Smith, E. E., Rentz, D. M., Johnson, K. A., et al. (2017) · Neurology · doi:10.1212/wnl.0000000000004059 · Cited by 145 · cited 1×
“Decrease of default-mode network (DMN) functional connectivity has been found in prodromal stages of AD, which is associated with loss of gray matter volume in neocortex and hippocampus.(239,240) Reduced DMN connectivity only occurs in individuals with elevated baseline Aβ-PET indexes, accelerating cortical atrophy.”
BackgroundMicroglia: Key Elements in Neural Development, Plasticity, and Pathology
Eyo, U. B., & Dailey, M. E. (2013) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-013-9434-z · Cited by 144 · cited 3×
“These cells communicate with surrounding environments including neurons, astrocytes and blood vessels to maintain the development and homeostasis of the CNS.(163,164) When microglia recognize the insults of the CNS, they respond to the injury or invasion by a morphological change, resulting in cell enlargement and mig…”
BackgroundWu, Y., Du, S., Johnson, J. L., Tung, H.-Y., Landers, C. T., Liu, Y., Seman, B. G., Wheeler, R. T., Costa-Mattioli, M., Kheradmand, F., et al. (2019) · Nature Communications · doi:10.1038/s41467-018-07991-4 · Cited by 143 · cited 2×
“albicans from brains in mice.(408) Together, the underlying mechanisms of Aβ peptides exerting their anti-microbial activity including interation with membranes and disruption of membrane integrity; stimulation of phagocytosis by inducing cytokines or altering microorganisms’ conformation.”
BackgroundDominantly Inherited Alzheimer Network: facilitating research and clinical trials
Moulder, K. L., Snider, B., Mills, S. L., Buckles, V. D., Santacruz, A. M., Bateman, R. J., & Morris, J. C. (2013) · Alzheimer's Research & Therapy · doi:10.1186/alzrt213 · Cited by 142 · cited 4×
“In 2012, DIAN-TU launched the first prevention trial focusing on two drugs: gantenerumab (against Aβ aggregates) and solanezumab (against soluble Aβ monomers).(337) The data showed that gantenerumab had a positive impact on the reduction of cortical amyloid, leading to its further study by an exploratory open-label ex…”
BackgroundInfluentialRegulation of microglia development and homeostasis.
Greter, M., & Merad, M. (2013) · Glia · doi:10.1002/glia.22408 · Cited by 141 · cited 3×
“Microglia comprise around 10–15% of all glial cells, which are the resident macrophages within the CNS.(161) In a healthy adult brain, microglia are in a resting state and highly ramified morphology with small somas.”
BackgroundA Physiological Role for Amyloid-β Protein: Enhancement of Learning and Memory
Morley, J. E., Farr, S. A., Banks, W. A., Johnson, S. N., Yamada, K. A., & Xu, L. (2010) · Journal of Alzheimer's Disease · doi:10.3233/jad-2010-1230 · Cited by 141
Miklossy, J. (2016) · Journal of Alzheimer’s Disease · doi:10.3233/jad-160451 · Cited by 140 · cited 1×
“This idea fits with the findings that HSV1 and Borrelia DNA have been found in plaque cores of AD brains.(400,401) Aβ peptides are able to interact and entrap various bacterial strains and viruses, such as HSV1 and HSV6, block their entry into the host cells to replicate.”
ResultFluorodeoxyglucose metabolism associated with tau‐amyloid interaction predicts memory decline
Hanseeuw, B. J., Betensky, R. A., Schultz, A. P., Papp, K. V., Mormino, E. C., Sepulcre, J., Bark, J. S., Cosio, D. M., LaPoint, M., Chhatwal, J. P., et al. (2017) · Annals of Neurology · doi:10.1002/ana.24910 · Cited by 140
Plasma amyloid beta measurements - a desired but elusive Alzheimer's disease biomarker
Toledo, J. B., Shaw, L. M. J., & Trojanowski, J. Q. (2013) · Alzheimer s Research & Therapy · doi:10.1186/alzrt162 · Cited by 139
Increased CSF APPs-α levels in patients with Alzheimer disease treated with acitretin
Endres, K., Fahrenholz, F., Lotz, J., Hiemke, C., Teipel, S. J., Lieb, K., Tüscher, O., & Fellgiebel, A. (2014) · Neurology · doi:10.1212/wnl.0000000000001017 · Cited by 138
Sugioka, K., Nakano, M., Totsune, H., Minakami, H., Tero‐Kubota, S., & Ikegami, Y. (1988) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/0005-2728(88)90014-x · Cited by 137 · cited 1×
“Mitochondria are also the major source of oxidative stress because the inevitable leakage of electrons at complex I and complex III of the electron-transport chain to produce reactive oxygen species (ROS).(213,214) Mitochondria generate approximately 90% of the cellular ROS.”
BackgroundSchneider, I., Reversé, D., Dewachter, I., Ris, L., Caluwaerts, N., Kuipéri, C., Gilis, M., Geerts, H., Kretzschmar, H. A., Godaux, E., et al. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m010977200 · Cited by 137
Yuan, J., Venkatraman, S., Zheng, Y., McKeever, B. M., Dillard, L. W., & Singh, S. B. (2013) · Journal of Medicinal Chemistry · doi:10.1021/jm301659n · Cited by 135
Kostylev, M. A., Kaufman, A. C., Nygaard, H. B., Patel, P., Haas, L. T., Gunther, E. C., Vortmeyer, A., & Strittmatter, S. M. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.643577 · Cited by 133 · cited 1×
“Cellular prion protein (PrPC) has been found as a receptor for toxic Aβ oligomers to induce LTP loss and cognitive impairment in AD model mice.(126,127) PrPC has been also detected in Aβ plaques in Alzheimer’s patients, which activates Fyn kinase and phosphorylates tau by the GluN2B subunit of NMDARs.”
BackgroundBACE1 Cleavage Site Selection Critical for Amyloidogenesis and Alzheimer's Pathogenesis
Zhang, S., Wang, Z., Cai, F., Zhang, M., Wu, Y., Zhang, J., & Song, W. (2017) · Journal of Neuroscience · doi:10.1523/jneurosci.0340-17.2017 · Cited by 133 · cited 1×
“The beta site APP cleaving enzyme 1 (BACE1), the β-secretase, and its homolog BACE2, the θ-secretase, also contribute to the non-amyloidogenic pathway.(7,8) Under physiological conditions, BACE1 predominantly processes APP at the Aβ Glu(11) β-secretase site to generate C89, and γ-secretase cleaves C89 to produce a tru…”
BackgroundSelf-citationAutophagy Dysfunction in Alzheimer’s Disease: Mechanistic Insights and New Therapeutic Opportunities
Di Meco, A., Curtis, M. E., Lauretti, E., & Praticò, D. (2020) · Biological Psychiatry · doi:10.1016/j.biopsych.2019.05.008 · Cited by 133 · cited 1×
“In addition, the complex of APP and γ-secretases was found in autophagosomes, suggesting the role of authophgic pathway in the generation of Aβ peptides.(494) Autophagy is also required for Aβ secretion.”
BackgroundTraditional Chinese Medicines in Treatment of Patients with Type 2 Diabetes Mellitus
Xie, W., Zhao, Y., & Zhang, Y. (2011) · Evidence-based Complementary and Alternative Medicine · doi:10.1155/2011/726723 · Cited by 132
Self-citationNew developments on the role of NMDA receptors in Alzheimer's disease
Malinow, R. (2012) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2011.09.001 · Cited by 132 · cited 1×
“Thus, Aβ accumulation inhibited the synaptic transmission, resulting in early cognitive impairment.(224) Aβ-induced LTD is also caused by inhibiting glutamate uptake and stimulating glutamate releasing, which evently elevates glutamate levels in the synapse cleft.”
BackgroundWithin-patient correspondence of amyloid-β and intrinsic network connectivity in Alzheimer’s disease
Myers, N., Pasquini, L., Göttler, J., Grimmer, T., Koch, K., Ortner, M., Neitzel, J., Mühlau, M., Förster, S., Kurz, A., et al. (2014) · Brain · doi:10.1093/brain/awu103 · Cited by 132
Distinct transcriptional regulation and function of the human BACE2 and BACE1 genes
Sun, X., Wang, Y., Qing, H., Christensen, M. A., Liu, Y., Zhou, W., Tong, Y., Xiao, C., Huang, Y., Zhang, S., et al. (2005) · The FASEB Journal · doi:10.1096/fj.04-3426com · Cited by 132
Self-citationHey, J. A., Yu, Y., Versavel, M., Abushakra, S. R., Kočiš, P., Power, A., Kaplan, P. L., Amedio, J. C., & Tolar, M. (2017) · Clinical Pharmacokinetics · doi:10.1007/s40262-017-0608-3 · Cited by 132
Amyloid-β effects on synapses and memory require AMPA receptor subunit GluA3
Reinders, N. R., Pao, Y., Renner, M., Matos, C. D. S., Lodder, T. R., Malinow, R., & Kessels, H. W. H. G. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1614249113 · Cited by 131
Impact of membrane curvature on amyloid aggregation
Terakawa, M. S., Lin, Y., Kinoshita, M., Kanemura, S., Itoh, D., Sugiki, T., Okumura, M., Ramamoorthy, A., & Lee, Y. (2018) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/j.bbamem.2018.04.012 · Cited by 131 · cited 1×
“In addition, It is well established that cholesteral-containing lipid membrane can influence Aβ seeding and aggregation.(70,71) As a nucleation process, cholesterol and GM1-rich lipid rafts accelerate Aβ aggregation by binding with Aβ to stabilize its structure.”
BackgroundHira, S., Saleem, U., Anwar, F., Sohail, M. F., Raza, Z., & Ahmad, B. (2019) · Biomolecules · doi:10.3390/biom9090441 · Cited by 131
Grothe, M. J., Heinsen, H., Amaro, E., Grinberg, L. T., & Teipel, S. J. (2015) · Cerebral Cortex · doi:10.1093/cercor/bhv062 · Cited by 130
Scheltens, P., Hallikainen, M., Grimmer, T., Duning, T., Gouw, A. A., Teunissen, C. E., Wink, A. M., Maruff, P., Harrison, J., van Baal, C. M., et al. (2018) · Alzheimer's Research & Therapy · doi:10.1186/s13195-018-0431-6 · Cited by 129
Basal forebrain atrophy correlates with amyloid β burden in Alzheimer's disease
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Spitzer, P., Condic, M., Herrmann, M., Oberstein, T. J., Scharin-Mehlmann, M., Gilbert, D. F., Friedrich, O., Grömer, T., Kornhuber, J., Lang, R., et al. (2016) · Scientific Reports · doi:10.1038/srep32228 · Cited by 128
Tariot, P. N., Lopera, F., Langbaum, J. B., Thomas, R. G., Hendrix, S., Schneider, L. S., Rios‐Romenets, S., Giraldo, M., Acosta, N., Tobon, C., et al. (2018) · Alzheimer's & Dementia: Translational Research & Clinical Interventions · doi:10.1016/j.trci.2018.02.002 · Cited by 128 · cited 2×
“In 2012, DIAN-TU launched the first prevention trial focusing on two drugs: gantenerumab (against Aβ aggregates) and solanezumab (against soluble Aβ monomers).337 The data showed that gantenerumab had a positive impact on the reduction of cortical amyloid, leading to its further study by an exploratory open-label exte…”
BackgroundNLRP3 inflammasome as a novel therapeutic target for Alzheimer’s disease
Zhang, Y., Dong, Z., & Song, W. (2020) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-0145-7 · Cited by 128
Self-citationShafi, O. (2016) · BMC Neurology · doi:10.1186/s12883-016-0765-2 · Cited by 125 · cited 1×
“In addition, recent studies show that AD patients have significantly lower incidences of several types of cancers, including skin cancer, lung cancer, breast cancer and bladder cancer.(366,367) Aβ has been demonstrated to inhibit tumor cell growth.”
ResultHigh molecular weight amyloid β 1‐42 oligomers induce neurotoxicity via plasma membrane damage
Yasumoto, T., Takamura, Y., Tsuji, M., Watanabe‐Nakayama, T., Imamura, K., Inoue, H., Nakamura, S., Inoue, T., Kimura, A., Yano, S., et al. (2019) · The FASEB Journal · doi:10.1096/fj.201900604r · Cited by 124
Chakrabarti, S., Munshi, S., Banerjee, K., Thakurta, I. G., Sinha, M. S., & Bagh, M. B. (2011) · Europe PMC (PubMed Central) · Cited by 122
New Insights in the Amyloid-Beta Interaction with Mitochondria
Spuch, C., Ortolano, S., & Fernández-Balbuena, C. N. (2012) · Journal of Aging Research · doi:10.1155/2012/324968 · Cited by 121 · cited 1×
“APP and Aβ can be imported into mitochondria, where they can interact with mitochondrial components, impair ATP production, and increase oxidative damage.(481,482) Antioxidants such as lipoic acid,(483) Amyloid β-based therapy for Alzheimer’s.”
BackgroundHaas, L. T., Salazar, S. V., Smith, L. M., Zhao, H. R., Cox, T. O., Herber, C. S., Degnan, A. P., Balakrishnan, A. S., Macor, J. E., Albright, C. F., et al. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.06.023 · Cited by 121
Human cerebral organoids establish subcortical projections in the mouse brain after transplantation
Dong, X., Xu, S., Chen, X., Tao, M., Tang, X.-Y., Fang, K.-H., Xu, M., Pan, Y., Chen, Y., He, S., et al. (2020) · Molecular Psychiatry · doi:10.1038/s41380-020-00910-4 · Cited by 121 · cited 1×
“In addition, transplantation of brain organoids may be a novel way to recover neuronal function and neural network after neuronal death during AD.(536) However, some limitations still exist and will need to be improved upon.”
BackgroundKazim, S. F., Seo, J. H., Bianchi, R., Larson, C. S., Sharma, A., Wong, R. K. S., Gorbachev, K., & Pereira, A. C. (2021) · eNeuro · doi:10.1523/eneuro.0418-20.2020 · Cited by 120 · cited 1×
“In contrast, Aβ and tau have antagonistic effects on neural circuit.(149) Tau induces the profound silencing of circuits by blocking Aβ-dependent hyperactivity in the cortex.”
BackgroundPanchal, M., Loeper, J., Cossec, J., Perruchini, C., Lazar, A. N., Pompon, D., & Duyckaerts, C. J. (2009) · Journal of Lipid Research · doi:10.1194/jlr.m001859 · Cited by 118 · cited 1×
“In addition, It is well established that cholesteral-containing lipid membrane can influence Aβ seeding and aggregation.(70,71) As a nucleation process, cholesterol and GM1-rich lipid rafts accelerate Aβ aggregation by binding with Aβ to stabilize its structure.”
BackgroundPredicting progression from normal cognition to mild cognitive impairment for individuals at 5 years
Albert, M., Zhu, Y., Moghekar, A., Mori, S., Miller, M. I., Soldan, A., Pettigrew, C., Selnes, O., Li, S., & Wang, M.-C. (2018) · Brain · doi:10.1093/brain/awx365 · Cited by 118
Findings of Efficacy, Safety, and Biomarker Outcomes of Atabecestat in Preclinical Alzheimer Disease
Sperling, R. A., Henley, D. B., Aisen, P. S. S., Raman, R., Donohue, M., Ernstrom, K. B., Rafii, M. S., Streffer, J. R., Shi, Y., Karcher, K., et al. (2021) · JAMA Neurology · doi:10.1001/jamaneurol.2020.4857 · Cited by 117
ElAli, A., & Rivest, S. (2013) · Frontiers in Physiology · doi:10.3389/fphys.2013.00045 · Cited by 115
Association of cancer and Alzheimer's disease risk in a national cohort of veterans
Frain, L., Swanson, D., Cho, K., Gagnon, D., Lu, K. P., Betensky, R. A., & Driver, J. (2017) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2017.04.012 · Cited by 115 · cited 1×
“In addition, recent studies show that AD patients have significantly lower incidences of several types of cancers, including skin cancer, lung cancer, breast cancer and bladder cancer.(366,367) Aβ has been demonstrated to inhibit tumor cell growth.”
ResultJackson, R. J., Rudinskiy, N., Herrmann, A. G., Croft, S., Kim, J. M., Petrova, V., Ramos‐Rodríguez, J. J., Pitstick, R., Wegmann, S., García-Alloza, M., et al. (2016) · European Journal of Neuroscience · doi:10.1111/ejn.13442 · Cited by 114
Spurrier, J., Nicholson, L., Fang, X. T., Stoner, A. J., Toyonaga, T., Holden, D., Siegert, T. R., Laird, W., Allnutt, M. A., Chiasseu, M., et al. (2022) · Science Translational Medicine · doi:10.1126/scitranslmed.abi8593 · Cited by 114
Synaptic transmission block by presynaptic injection of oligomeric amyloid beta
Moreno, H., Yu, E., Pigino, G. F., Hernandez, A. I., Kim, N., Moreira, J. E., Sugimori, M., & Llinás, R. R. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0900944106 · Cited by 113 · cited 1×
“Recently, two parallel studies have further investigated the underlying mechanism of the Aβ’s detrimental effect over synaptic transmission.(87,88) They found that intracellular administration of the AβOs rather than administration of the AβOs at the extracellular level altered the synaptic transmission and fast axona…”
BackgroundWalker, L. C. (2020) · Free Neuropathology · doi:10.17879/freeneuropathology-2020-3025 · Cited by 113
Davtyan, H., Ghochikyan, A., Petrushina, I., Hovakimyan, A., Davtyan, A., Poghosyan, A., Marleau, A. M., Movsesyan, N., Kiyatkin, A., Rasool, S., et al. (2013) · The Journal of Neuroscience · doi:10.1523/jneurosci.4672-12.2013 · Cited by 112 · cited 2×
“In the preclinical studies, ACI-24 was shown to generate high titers of anti-Aβ IgG1 and IgG2b antibodies and improve novel object recognition in AD mice.(324) Its Phase 2 trials have been started, in which ACI-24 becomes the first anti-Aβ vaccine to be evaluated for treating AD in Down’s syndrome patients.”
BackgroundAβ Oligomers Induce Glutamate Release from Hippocampal Neurons
Brito‐Moreira, J., Paula-Lima, A. C., Bomfim, T. R., de Oliveira, F. F., Sepúlveda, F. J., Mello, F. G. D., Aguayo, L. G., Panizzutti, R., & Ferreira, S. T. (2011) · Current Alzheimer Research · doi:10.2174/156720511796391917 · Cited by 111 · cited 1×
“Aβ-induced LTD is also caused by inhibiting glutamate uptake and stimulating glutamate releasing, which evently elevates glutamate levels in the synapse cleft.(222,225,227,228) An increase of glutamate activated GluN2B-bearing NMDARs, which further led to calcium-induced LTD and synaptic depression.”
BackgroundLacosta, A.-M., Pascual-Lucas, M., Pesini, P., Casabona, D., Pérez-Grijalba, V., Marcos-Campos, I., Sarasa, L., Canudas, J., Badi, H., Monleón, I., et al. (2018) · Alzheimer's Research & Therapy · doi:10.1186/s13195-018-0340-8 · Cited by 111 · cited 1×
“Another vaccine called ABvac40 targets the C-terminus of Aβ peptides and is also currently being evaluated in Phase 2 clinical studies.(326) UB-311 consists of the Aβ1-14 peptides in combination with a Th-cell epitope, which was designed to specifically stimulate Th2 cells regulatory immune responses over Th1-mediated…”
BackgroundTau binding protein CAPON induces tau aggregation and neurodegeneration
Hashimoto, S., Matsuba, Y., Kamano, N., Mihira, N., Sahara, N., Takano, J., Muramatsu, S.-I., Saido, T. C., & Saito, T. (2019) · Nature Communications · doi:10.1038/s41467-019-10278-x · Cited by 111
Cenini, G., Rüb, C., Bruderek, M., & Voos, W. (2016) · Molecular Biology of the Cell · doi:10.1091/mbc.e16-05-0313 · Cited by 111
Receptors, Ion Channels, and Signaling Mechanisms Underlying Microglial Dynamics
Madry, C., & Attwell, D. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.r115.637157 · Cited by 109 · cited 3×
“These cells communicate with surrounding environments including neurons, astrocytes and blood vessels to maintain the development and homeostasis of the CNS.(163,164) When microglia recognize the insults of the CNS, they respond to the injury or invasion by a morphological change, resulting in cell enlargement and mig…”
BackgroundSuárez‐Calvet, M., Capell, A., Araque Caballero, M. Á., Morenas‐Rodríguez, E., Fellerer, K., Franzmeier, N., Kleinberger, G., Eren, E., Deming, Y., Piccio, L., et al. (2018) · EMBO Molecular Medicine · doi:10.15252/emmm.201809712 · Cited by 109 · cited 1×
“It has been observed that the CSF level of progranulin elevates as early as ten years before the presentation of symptoms in patients with familial or sporadic AD.(544) Neurogranin is expressed in the cortex and hippocampus, the brain areas most affected by AD.”
BackgroundMurakami, K., Murata, N., Ozawa, Y., Kinoshita, N., Irie, K., Shirasawa, T., & Shimizu, T. (2011) · Journal of Alzheimer s Disease · doi:10.3233/jad-2011-101971 · Cited by 108
Increased Expression of TREM2 in Peripheral Blood of Alzheimer's Disease Patients
Hu, N., Tan, M., Yu, J., Sun, L., Tan, L., Wang, Y.-L., Jiang, T., & Tan, L. (2013) · Journal of Alzheimer s Disease · doi:10.3233/jad-130854 · Cited by 108 · cited 1×
“Increased TERM2 experession has been found in human AD blood, indicating the important role of peripheral TREM2 in Alzheimer’s pathogenesis.(176,177) Using flow cytometry identified that these cells also contained high levels of CD45, Ly6c, and CD11b, which highly express in peripheral macrophages as well.”
BackgroundDeng, Y., Wang, Z., Wang, R., Zhang, X., Zhang, S., Wu, Y., Staufenbiel, M., Cai, F., & Song, W. (2013) · European Journal of Neuroscience · doi:10.1111/ejn.12235 · Cited by 108
Self-citationHernandez, P., Lee, G., Sjoberg, M., & Maccioni, R. B. (2009) · Journal of Alzheimer's Disease · doi:10.3233/jad-2009-0933 · Cited by 107
Hughes, C., Choi, M. L., Yi, J.-H., Kim, S.-C., Drews, A., George-Hyslop, P. S., Bryant, C., Gandhi, S., Cho, K., & Klenerman, D. (2020) · Communications Biology · doi:10.1038/s42003-020-0792-9 · Cited by 107 · cited 1×
“Astrocytes response to Aβ aggregates in a TLR-dependent manner, which further activates the target genes to produce proinflammatory factors.(185,186) The excessive production of proinflammatory cytokines such as TNF-α or IFN-γ modulated the APP processing in astrocytes, leading to the increased Aβ levels and toxicity.”
BackgroundChang, L. Y. L., Lowe, J., Ardiles, A., Lim, J., Grey, A. C., Robertson, K., Danesh‐Meyer, H., Palacios, A. G., & Acosta, M. L. (2014) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2013.06.004 · Cited by 106
Miyamoto, T., Stein, L. R., Thomas, R., Djukic, B., Taneja, P., Knox, J. A., Vossel, K. A., & Mucke, L. (2017) · Molecular Neurodegeneration · doi:10.1186/s13024-017-0176-x · Cited by 106 · cited 1×
“A recent study proposed that the phosphorylation of tau at Tyr18 by Fyn kinase also blocked Aβ toxicity.(139,140) Aβ promoted the phosphorylation and activation of Fyn kinase, which further migrated into dendritic spines, leading to synaptic impariment.”
Background
Research works printed but not linked: 1
- Walker, L. C. Abeta plaques. Free Neuropathol. 1, 31 (2020).
Cited by
Sorted by citations
Zhang, J., Zhang, Y., Wang, J., Xia, Y., Zhang, J., & Chen, L. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01911-3 · Cited by 1,138
Self-citationThe gut microbiota-immune-brain axis: therapeutic implications
O’Riordan, K. J., Moloney, G. M., Keane, L., Clarke, G., & Cryan, J. F. (2025) · Cell Reports Medicine · doi:10.1016/j.xcrm.2025.101982 · Cited by 333
“115 The disease progresses from the transentorhinal cortex to the hippocampus and cortical areas.”
Tumilaar, S. G., Hardianto, A., Dohi, H., & Kurnia, D. (2024) · Journal of Chemistry · doi:10.1155/2024/5594386 · Cited by 356
The role of inflammasomes in human diseases and their potential as therapeutic targets
Yao, J., Sterling, K., Wang, Z., Zhang, Y., & Song, W. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01687-y · Cited by 260
“205 It is characterized by the formation of neuritic plaques and neuro fi - brillary tangles (NFTs) in the brain.”
BackgroundSelf-citationUpdates in Alzheimer's disease: from basic research to diagnosis and therapies
Liu, E., Zhang, Y., & Wang, J. (2024) · Translational Neurodegeneration · doi:10.1186/s40035-024-00432-x · Cited by 241
“The extracellular accumulation of insoluble Aβ can also activate neurotoxic cascades that ultimately lead to cytoskeletal changes, neuronal dysfunction and neural death [217, 218].”
BackgroundSelf-citation
Metadata
- Authors
- Zhang, Y., Chen, H., Li, R., Sterling, K., & Song, W.
- Affiliations
- Capital Medical University (CN)
- Wenzhou Medical University (CN)
- University of British Columbia (CA)
- Corresponding author
- Zhang, Yun
- Song, Weihong
- Venue
- Signal Transduction and Targeted Therapy
- Published
- 2023-06-30
- Volume
- 8
- Issue
- 1
- Pages
- 248-248
- ISSN
- 2059-3635 (ISSN-L)
- PMC
- PMC10310781
- OpenAlex
- W4382601497
- Cited by
- 988
- References
- 562
- Citations by year
- 2026: 278 · 2025: 422 · 2024: 257 · 2023: 30
- FWCI
- 35.22
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Signal Transduction and Targeted Therapy (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Natural Science Foundation of China (82150710557, 82201576)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Pharmacology (medical) › Cholinesterase and Neurodegenerative Diseases
- Keywords
- amyloid-beta, Alzheimer's disease, amyloid hypothesis, anti-amyloid therapy, neuritic plaques, Alzheimer's disease prevention, Alzheimer's disease treatment, Alzheimer's disease diagnosis
- MeSH terms
- Alzheimer Disease, Humans, Amyloid beta-Peptides, Plaque, Amyloid
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