Role of Oxidative Damage in Alzheimer’s Disease and Neurodegeneration: From Pathogenic Mechanisms to Biomarker Discovery

In the paper

“All of these markers of OS have been described as an early alteration in the AD brain, and this concept has been used in the past to support the ‘oxidative stress hypothesis’ in the pathogenesis of AD [20,28,29,30].”

What the sources say

• Partly supported

  The Discussion reports that lipid peroxidation increased before substantial amyloid deposition in Tg2576 mice, supporting an early role for oxidative stress in this AD model. The paper also notes increased lipid-peroxidation markers in human AD brain regions, but our copy does not describe protein or nucleic acid oxidation as early alterations in the AD brain. Its early-timing finding is from mice, not human AD brains. (LLM, conf=0.87)

  cites [20] Uryu, 2001, Increased Lipid Peroxidation Precedes Amyloid Plaque Formation in an Animal Model of Alzheimer Amyloidosis, J. Neurosci. sourceExperimental — accuracy not yet measured
• Not checked yetcites [28] Jellinger, 1990, Brain iron and ferritin in Parkinson’s and Alzheimer’s diseases, J. Neural Transm. source
• Not checked yetcites [29] Markesbery, 1997, Oxidative Stress Hypothesis in Alzheimer’s Disease, Free. Radic. Biol. Med. source
• Partly supported

  Section 2 identifies protein damage and lipid-peroxidation products in AD, and §2.1 identifies increased 8OHG, a nucleic-acid oxidation marker. Section 2.1 also says oxidative damage can precede other abnormalities, supporting the broader early-oxidative-stress account. It does not establish that each listed marker is itself an early alteration; it distinguishes protein crosslinking as a record of past damage from 8OHG as a marker of more immediate damage. (LLM, conf=0.84)

  cites [30] Smith, 2000, Oxidative stress in Alzheimer’s disease, Biochim. et Biophys. Acta (BBA) Mol. Basis Dis. sourceExperimental — accuracy not yet measured

In the paper

“Excessive Ca2+ accumulation into mitochondria leads to decreased mitochondrial membrane potential and increased ROS production in the same AD mouse model [67,68,70].”

What the sources say

• Partly supported

  The Results report lowered mitochondrial membrane potential and higher mitochondrial superoxide in human iPSC-derived PS1P117L AD neurons. They do not establish that excessive mitochondrial Ca2+ accumulation caused those changes, and the neurons are not the APP/PS1 mouse model named in the claim. The paper’s mouse experiments use a 3xTg-AD model. (LLM, conf=0.88)

  cites [67] Oka, 2016, Human mitochondrial transcriptional factor A breaks the mitochondria-mediated vicious cycle in Alzheimer’s disease, Sci. Rep. sourceExperimental — accuracy not yet measured
• Partly supported

  The “Aging and perturbed neuronal calcium homeostasis” section links mitochondrial Ca2+ overload, membrane depolarization, and ROS to neurodegeneration, including AD. It does not report these outcomes in APP/PS1 mice or establish that mitochondrial Ca2+ accumulation caused both reduced membrane potential and increased ROS in that model. No page number is available in our copy. (LLM, conf=0.84)

  cites [68] Mattson, 2007, Calcium and neurodegeneration, Aging Cell sourceExperimental — accuracy not yet measured
• Partly supported

  The Results (Figure 6, p. 17049) show decreased mitochondrial membrane potential in oxidized neurons and neurites of APP/PS1 mice. The Discussion says calcium dysregulation, oxidative stress, and mitochondrial dysfunction may be linked, but that their sequence remains to be determined. It does not establish excessive calcium accumulation in mitochondria or show that calcium causes the membrane-potential decrease and increased ROS production. (LLM, conf=0.88)

  cites [70] Xie, 2013, Mitochondrial alterations near amyloid plaques in an Alzheimer’s disease mouse model, J. Neurosci. sourceExperimental — accuracy not yet measured

In the paper

“In AD, Aβ can act as DAMP and its interaction with microglia creates an oxidative and neuroinflammatory environment through an increased production of ROS and release of proinflammatory cytokines [107].”

What the sources say

• Supported

  Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [107] Venegas, 2016, Danger-associated molecular patterns in Alzheimer’s disease, J. Leukoc. Biol. source

In the paper

“uncovering important roles for HDAC1 in 8-oxoG repair and highlights the therapeutic potential of HDAC1 activation to counteract the functional decline in brain aging and neurodegeneration [126].”

What the sources say

• Supported

  The Abstract explicitly says HDAC1 has important roles in 8-oxoG repair and highlights the therapeutic potential of HDAC1 activation to counter functional decline in brain aging and neurodegeneration. The Introduction also reports that pharmacological activation reduced 8-oxoG lesions in aged and Alzheimer’s-model mice and alleviated cognitive deficits in the latter. (LLM, conf=0.95)

  cites [126] Pao, 2020, HDAC1 modulates OGG1-initiated oxidative DNA damage repair in the aging brain and Alzheimer’s disease, Nat. Commun. source

In the paper

“The most common cause of dementia is Alzheimer’s disease (AD), a progressive neurodegenerative disorder, affecting over 50 million people worldwide [4].”

What the sources say

• Not checked yetcites [4] Prince, 2016, Recent global trends in the prevalence and incidence of dementia, and survival with dementia, Alzheimer’s Res. Ther. source

In the paper

“the most studied pathogenic mechanism has been the “amyloid cascade hypothesis” proposed in 1991 by Hardy and Allsop, who suggested that inappropriate processing of amyloid-β (Aβ) precursor leads to the build-up of amyloid plaques, the formation of tau tangles, and ultimately to neuronal death [7].”

What the sources say

• Not checked yetcites [7] Hardy, 1991, Amyloid deposition as the central event in the aetiology of Alzheimer’s disease, Trends Pharmacol. Sci. source

In the paper

“The disease is irreversible and presents with neurodegeneration caused by toxic aggregation of extracellular amyloid plaques, and intracellular neurofibrillary tangles of hyperphosphorylated tau protein [5].”

What the sources say

• Not checked yetcites [5] Stelzmann, 1995, An english translation of alzheimer’s 1907 paper, “über eine eigenartige erkankung der hirnrinde”, Clin. Anat. source

In the paper

“Past and recent studies have demonstrated that oxidative damage is not only an early event in the pathogenesis of AD, occurring before the onset of clinical symptoms but also a factor contributing to the disease progression [17,18,19,20,21].”

What the sources say

• Not checked yetcites [17] Butterfield, 1997, β-Amyloid-Associated Free Radical Oxidative Stress and Neurotoxicity: Implications for Alzheimer’s Disease, Chem. Res. Toxicol. source
• Not checked yetcites [18] Butterfield, 2019, Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease, Nat. Rev. Neurosci. source
• Not checked yetcites [19] Nunomura, 2001, Oxidative Damage Is the Earliest Event in Alzheimer Disease, J. Neuropathol. Exp. Neurol. source
• Not checked yetcites [20] Uryu, 2001, Increased Lipid Peroxidation Precedes Amyloid Plaque Formation in an Animal Model of Alzheimer Amyloidosis, J. Neurosci. source
• Not checked yetcites [21] Ansari, 2011, NADPH-oxidase activation and cognition in Alzheimer disease progression, Free. Radic. Biol. Med. source

In the paper

“The brain is very susceptible to OS because it is rich in polyunsaturated fatty acids, has a high oxygen consumption and a high content of metals in particular, iron, that can catalyze oxidative reactions, in contrast, it has less antioxidant enzymes in comparison with other organs [28].”

What the sources say

• Not checked yetcites [28] Jellinger, 1990, Brain iron and ferritin in Parkinson’s and Alzheimer’s diseases, J. Neural Transm. source

In the paper

“Redox proteomic studies confirm previous results that carbonylated proteins are present in CSF of amnestic MCI patients compared with controls, and these proteins remain oxidized in the progression towards AD [40].”

What the sources say

• Not checked yetcites [40] Pupo, 2016, Oxidative signature of cerebrospinal fluid from mild cognitive impairment and Alzheimer disease patients, Free. Radic. Biol. Med. source

In the paper

“In AD, reactive microglia and astrocytes are associated with the amyloid plaques and respond to Aβ with the expression of pro-inflammatory cytokines [12,13,14].”

What the sources say

• Not checked yetcites [12] Mielke, 2011, Reactive Glia not only Associates with Plaques but also Parallels Tangles in Alzheimer’s Disease, Am. J. Pathol. source
• Not checked yetcites [13] Hanisch, 2007, Microglia: Active sensor and versatile effector cells in the normal and pathologic brain, Nat. Neurosci. source
• Not checked yetcites [14] Galimberti, 1999, α-MSH Peptides Inhibit Production of Nitric Oxide and Tumor Necrosis Factor-α by Microglial Cells Activated with β-Amyloid and Interferon γ, Biochem. Biophys. Res. Commun. source

In the paper

“In 2021, new recommendations for the clinical diagnosis of AD were proposed by the International working group, highlighting that the diagnosis of AD should be restricted to people who have positive biomarkers together with specific AD phenotypes. Cognitively unimpaired individuals who are only positive to biomarkers should be considered at-risk for progression to AD [10].”

What the sources say

• Not checked yetcites [10] Dubois, 2021, Clinical diagnosis of Alzheimer’s disease: Recommendations of the International Working Group, Lancet Neurol. source

In the paper

“Decreased levels of phosphatidylcholine, phosphatidylethanolamine and the phospholipid precursors, choline and ethanolamine, have been described in AD and are considered specific for the pathogenic mechanism of AD. The depletion of phospholipids in AD has been referred to an increase of ROS-mediated lipid peroxidation [29].”

What the sources say

• Not checked yetcites [29] Markesbery, 1997, Oxidative Stress Hypothesis in Alzheimer’s Disease, Free. Radic. Biol. Med. source

In the paper

“In the brains of individuals with AD and preclinical AD (i.e., evidence of Aβ and tau deposition in the brain without any clinical manifestation of the disease), as well as patients with MCI (a mild clinical impairment with no proof of underlying pathology with biomarkers), many oxidative damage products are measured, and numerous investigations have pointed to OS as a key and early player in the”

What the sources say

• Not checked yetcites [18] Butterfield, 2019, Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease, Nat. Rev. Neurosci. source
• Not checked yetcites [19] Nunomura, 2001, Oxidative Damage Is the Earliest Event in Alzheimer Disease, J. Neuropathol. Exp. Neurol. source

In the paper

“Following the new research framework (2018-NIA-AA-RF), AD is not defined by its clinical consequences but by its underlying pathology measured by lifetime biomarkers. Regardless of the presence of clinical symptoms, both Aβ and phosphorylated tau pathology are required for classification as AD, whereas Aβ deposition alone is an early sign, labelling the pathologic change towards AD [9].”

What the sources say

• Not checked yetcites [9] Carandini, 2019, Testing the 2018 NIA-AA research framework in a retrospective large cohort of patients with cognitive impairment: From biological biomarkers to clinical syndromes, Alzheimer’s Res. Ther. source

In the paper

“Further, activated microglia can respond to injured neurons in a neuroprotective manner and, afterwards, become toxic, contributing to neuroinflammation and neurodegeneration [15].”

What the sources say

• Not checked yetcites [15] Clark, 2015, Amyloid β: One of three danger-associated molecules that are secondary inducers of the proinflammatory cytokines that mediate A lzheimer’s disease, Br. J. Pharmacol. source

In the paper

“About 2–3% of AD cases are due to autosomal dominant mutations. The rest are sporadic cases and are prevalent in the aging population [8].”

What the sources say

• Not checked yetcites [8] Galimberti, 2010, Treatment of Alzheimers Disease: Symptomatic and Disease-Modifying Approaches, Curr. Aging Sci. source

In the paper

“Aβ oligomers can target and activate NMDAR leading to a rapid increase in neuronal calcium levels and ROS production in mature hippocampal neurons in culture [75].”

What the sources say

• Not checked yetcites [75] Velasco, 2007, Aβ Oligomers Induce Neuronal Oxidative Stress through an N-Methyl-D-aspartate Receptor-dependent Mechanism That Is Blocked by the Alzheimer Drug Memantine, J. Biol. Chem. source

In the paper

“During pathological activation of the NMDAR, memantine blocks excessive calcium entry through the channel and Aβ-induced OS, providing a specific biological mechanism for the therapeutic action of memantine.”

What the sources say

• Not checked yetcites [74] Robinson, 2006, Memantine: A Review of Its Use in Alzheimer’s Disease, Drugs source
• Not checked yetcites [75] Velasco, 2007, Aβ Oligomers Induce Neuronal Oxidative Stress through an N-Methyl-D-aspartate Receptor-dependent Mechanism That Is Blocked by the Alzheimer Drug Memantine, J. Biol. Chem. source

In the paper

“Besides, amyloid oligomers can access mitochondria, contributing to compromise their function and triggering a vicious circle in which it is not defined if the accumulation of Aβ came before mitochondrial declined function or after [67].”

What the sources say

• Not checked yetcites [67] Oka, 2016, Human mitochondrial transcriptional factor A breaks the mitochondria-mediated vicious cycle in Alzheimer’s disease, Sci. Rep. source

In the paper

“In this explanation, the mitochondrial function declines with age and leads to increased production of ROS [65,66].”

What the sources say

• Not checked yetcites [65] Swerdlow, 2004, A “mitochondrial cascade hypothesis” for sporadic Alzheimer’s disease, Med. Hypotheses source
• Not checked yetcites [66] Swerdlow, 2010, The Alzheimer’s Disease Mitochondrial Cascade Hypothesis, J. Alzheimer’s Dis. source

In the paper

“In the AD brain, mitochondria can be sources of ROS and also the target of OS, especially mitochondrial DNA (mtDNA) is susceptible to oxidative damage [19,53,63].”

What the sources say

• Not checked yetcites [19] Nunomura, 2001, Oxidative Damage Is the Earliest Event in Alzheimer Disease, J. Neuropathol. Exp. Neurol. source
• Not checked yetcites [53] Hirai, 2001, Mitochondrial Abnormalities in Alzheimer’s Disease, J. Neurosci. source
• Not checked yetcites [63] Lin, 2006, Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases, Nat. Cell Biol.

In the paper

“Aβ can be toxic on neuronal mitochondria and causes Ca2+ elevation, changes in mitochondrial size and shape in APP/PS1 AD mouse model [70].”

What the sources say

• Not checked yetcites [70] Xie, 2013, Mitochondrial alterations near amyloid plaques in an Alzheimer’s disease mouse model, J. Neurosci. source

In the paper

“These abnormalities are found in neurons lacking neurofibrillary tangles, suggesting that mitochondrial abnormalities are one of the earliest pathological changes in AD.”

What the sources say

• Not checked yetcites [53] Hirai, 2001, Mitochondrial Abnormalities in Alzheimer’s Disease, J. Neurosci. source

In the paper

“Glucose metabolism is dysregulated in AD and MCI and the metabolic rate of glucose is decreased in the brain of patients with senile dementia [18].”

What the sources say

• Not checked yetcites [18] Butterfield, 2019, Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease, Nat. Rev. Neurosci. source

In the paper

“It is demonstrated that there is a progressive age-related accumulation of oxidative damage to DNA in the human brain and that mtDNA is preferentially affected. The increased amount of 8-OHdG in mtDNA and nuclear DNA is demonstrated in the aging human brain and in AD [50,51,64].”

What the sources say

• Not checked yetcites [50] Mecocci, 1993, Oxidative damage to mitochondrial DNA shows marked age-dependent increases in human brain, Ann. Neurol. source
• Not checked yetcites [51] Mecocci, 1994, Oxidative damage to mitochondrial DNA is increased in Alzheimer’s disease, Ann. Neurol. source
• Not checked yetcites [64] Mecocci, 1997, Mitochondrial membrane fluidity and oxidative damage to mitochondrial DNA in aged and AD human brain, Mol. Chem. Neuropathol. source

In the paper

“Hirai et al. have demonstrated that oxidative damage marked by 8-OHdG and nitrotyrosine occurs in the neurons of AD patients. Morphometric analysis showed a reduction of mitochondria in these same neurons and an accumulation of mtDNA and mitochondrial proteins [53].”

What the sources say

• Not checked yetcites [53] Hirai, 2001, Mitochondrial Abnormalities in Alzheimer’s Disease, J. Neurosci. source

In the paper

“These results confirmed that mtDNA is a target of oxidative damage and that the increased damage to DNA contributes to AD and the neurodegenerative process [51,53].”

What the sources say

• Not checked yetcites [51] Mecocci, 1994, Oxidative damage to mitochondrial DNA is increased in Alzheimer’s disease, Ann. Neurol. source
• Not checked yetcites [53] Hirai, 2001, Mitochondrial Abnormalities in Alzheimer’s Disease, J. Neurosci. source

In the paper

“Recently, sirtuin 3 (SIRT3) defects have been considered to contribute to OS in AD mitochondria. Indeed, SIRT3 has been linked to dysregulation of mitochondrial DNA expression, ROS accumulation and neuronal damage in AD [76,77].”

What the sources say

• Not checked yetcites [76] Lee, 2017, SIRT3 deregulation is linked to mitochondrial dysfunction in Alzheimer’s disease, Aging Cell source
• Not checked yetcites [77] Zhang, 2020, Mitochondrial Sirtuin 3: New emerging biological function and therapeutic target, Theranostics source

In the paper

“To counterbalance the increase of OS that is characteristic in age-related neurodegenerative diseases antioxidant treatment are studied in experimental models and in human trials.”

In the paper

“NO X4 is the astrocytes isoform, and its levels are reported significantly elevated in astrocytes of patients with AD and APP/PS1 double-transgenic mouse model of AD [101].”

What the sources say

• Not checked yetcites [101] Park, 2021, NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer’s diseases, Redox Biol. source

In the paper

“Colocalization of reactive microglia with Aβ deposits is a hallmark of AD pathology and has been reported also in brains from AD mouse models [102,103].”

What the sources say

• Not checked yetcites [102] Sarlus, 2017, Microglia in Alzheimer’s disease, J. Clin. Investig. source
• Not checked yetcites [103] Schwabe, 2020, Shifting paradigms: The central role of microglia in Alzheimer’s disease, Neurobiol. Dis. source

In the paper

“The levels of two products of oxidative damage, 4-HNE and MDA, were also significantly elevated, suggesting that the elevation of NOX4 promotes the impairment of mitochondrial metabolism, mitochondrial ROS production and fragmentation in human astrocytes [101].”

What the sources say

• Not checked yetcites [101] Park, 2021, NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in Alzheimer’s diseases, Redox Biol. source

In the paper

“Another Nrf2 activating compound is Centella asiatica extracts, which can activate Nrf2 in neuroblastoma cells, isolated primary neurons and in the brains of AD and aging mouse models. This activation improved mitochondrial and cognitive function, and enhanced synaptic density [113,114,115].”

What the sources say

• Not checked yetcites [113] Brandes, M.S., and Gray, N.E. (2020). NRF2 as a Therapeutic Target in Neurodegenerative Diseases. ASN Neuro, 12. source
• Not checked yetcites [114] Gray, 2018, Centella asiatica attenuates hippocampal mitochondrial dysfunction and improves memory and executive function in β-amyloid overexpressing mice, Mol. Cell. Neurosci. source
• Not checked yetcites [115] Matthews, D.G., Caruso, M., Murchison, C.F., Zhu, J.Y., Wright, K.M., Harris, C.J., Gray, N.E., Quinn, J.F., and Soumyanath, A. (2019). Centella Asiatica Improves Memory and Promotes Antioxidative Signaling in 5XFAD Mice. Antioxidants, 8. source

In the paper

“NOX activation is evident in the AD brain, in addition NOX2 is highly expressed in microglia [108,109].”

What the sources say

• Not checked yetcites [108] Shimohamaa, 2000, Activation of NADPH Oxidase in Alzheimer’s Disease Brains, Biochem. Biophys. Res. Commun. source
• Not checked yetcites [109] Geng, 2020, Nox2 dependent redox-regulation of microglial response to amyloid-β stimulation and microgliosis in aging, Sci. Rep. source

In the paper

“Regarding the relation of TREM2 with OS, it has been supposed that a down-regulation of microglial TREM2 expression and signaling might be one of the major pathogenetic mechanisms in sporadic cases of AD in which advanced age, OS, neuroinflammation contribute to the suppression of wild-type TREM2, considering that TREM2 mutation is rare in humans [123].”

What the sources say

• Not checked yetcites [123] Liu, 2020, Trem2 promotes anti-inflammatory responses in microglia and is suppressed under pro-inflammatory conditions, Hum. Mol. Genet. source

In the paper

“Oxidative damage to RNA in EC, hippocampus, subiculum, and temporal neocortex of subjects with AD has been described. The levels of 8-OHdG increase early before pathological changes occur, and this can explain that the selective vulnerability of neurons in the EC during AD may be related to the vulnerability of these particular neurons to oxidative damage [19].”

What the sources say

• Not checked yetcites [19] Nunomura, 2001, Oxidative Damage Is the Earliest Event in Alzheimer Disease, J. Neuropathol. Exp. Neurol. source

In the paper

“The pioneering studies, conducted to validate the early changes of products of oxidative damage, found in specimens of AD patients, in a transgenic mouse model (Tg2576) of AD amyloidosis, dated back more than 20 years [20,124].”

What the sources say

• Not checked yetcites [20] Uryu, 2001, Increased Lipid Peroxidation Precedes Amyloid Plaque Formation in an Animal Model of Alzheimer Amyloidosis, J. Neurosci. source
• Not checked yetcites [124] Pratico, 1998, Increased F 2 -isoprostanes in Alzheimer’s disease: Evidence for enhanced lipid peroxidation in vivo, FASEB J. source

In the paper

“Abnormalities in iron homeostasis in brain tissue can increase ROS production, causing noxious oxidative damage to sensitive cellular structures, and trigger a new cell death process called ferroptosis [98,99].”

What the sources say

• Not checked yetcites [98] Li, 2020, Ferroptosis: Past, present and future, Cell Death Dis. source
• Not checked yetcites [99] Yan, 2021, Ferroptosis: Mechanisms and links with diseases, Signal Transduct. Target. Ther. source

In the paper

“γ-GC may also lower inflammation and enhance Aβ plaque clearance in vivo as suggested by cytokines and matrix metalloproteinase levels in the brain.”

What the sources say

• Not checked yetcites [134] Liu, 2020, Supplementation with γ-glutamylcysteine (γ-GC) lessens oxidative stress, brain inflammation and amyloid pathology and improves spatial memory in a murine model of AD, Neurochem. Int. source

In the paper

“MITOL is an integral mitochondrial outer membrane protein which regulates mitochondrial functions and morphology [131].”

What the sources say

• Not checked yetcites [131] Takeda, 2021, Mitochondrial ubiquitin ligase alleviates Alzheimer’s disease pathology via blocking the toxic amyloid-β oligomer generation, Commun. Biol. source

In the paper

“Glutathione (GSH) is a cellular antioxidant, and its depletion has been observed in AD [133].”

What the sources say

• Not checked yetcites [133] Haddad, M., Hervé, V., Ben Khedher, M.R., Rabanel, J.-M., and Ramassamy, C. (2021). Glutathione: An Old and Small Molecule with Great Functions and New Applications in the Brain and in Alzheimer’s Disease. Antioxid. Redox Signal., 35. source

In the paper

“Aβ pathology was reduced, and AChE activity was improved in APP/S1 mice on the γ-GC diet compared to APP/PS1 mice fed a standard chow diet.”

What the sources say

• Not checked yetcites [134] Liu, 2020, Supplementation with γ-glutamylcysteine (γ-GC) lessens oxidative stress, brain inflammation and amyloid pathology and improves spatial memory in a murine model of AD, Neurochem. Int. source

In the paper

“The authors report that the diet with γ-GC lowered the levels of brain lipid peroxidation, protein carbonyls and apoptosis, and maintain antioxidant status in APP/PS1 mice.”

What the sources say

• Not checked yetcites [134] Liu, 2020, Supplementation with γ-glutamylcysteine (γ-GC) lessens oxidative stress, brain inflammation and amyloid pathology and improves spatial memory in a murine model of AD, Neurochem. Int. source

In the paper

“sirtuin (SIRT) 1 can also bind the class I histone deacetylase HDAC1, deacetylate HDAC1 and stimulate its enzymatic activity [128].”

What the sources say

• Not checked yetcites [128] Dobbin, 2013, SIRT1 collaborates with ATM and HDAC1 to maintain genomic stability in neurons, Nat. Neurosci. source

In the paper

“Stojakovic et al. observed that mitochondrial respiratory chain complex I might be a therapeutic target in AD [129].”

What the sources say

• Not checked yetcites [129] Stojakovic, 2021, Partial inhibition of mitochondrial complex I ameliorates Alzheimer’s disease pathology and cognition in APP/PS1 female mice, Commun. Biol. source

In the paper

“HDAC1-deficient mice show DNA damage accumulation and cognitive impairment during aging [126].”

What the sources say

• Not checked yetcites [126] Pao, 2020, HDAC1 modulates OGG1-initiated oxidative DNA damage repair in the aging brain and Alzheimer’s disease, Nat. Commun. source

In the paper

“Blood-based biomarkers are not available for AD and the potential ones are derived from Aβ and Tau [137].”

What the sources say

• Not checked yetcites [137] Nakamura, 2018, High performance plasma amyloid-β biomarkers for Alzheimer’s disease, Nat. Cell Biol.

In the paper

“this work showed elevated 8-oxoG along with reduced HDAC1 activity and downregulation of a gene set critical for brain function in the 5XFAD mouse model of AD”

What the sources say

• Not checked yetcites [126] Pao, 2020, HDAC1 modulates OGG1-initiated oxidative DNA damage repair in the aging brain and Alzheimer’s disease, Nat. Commun. source

In the paper

“Taken together, the data suggest that CP2 treatment induces multiple protective mechanisms including autophagy, anti-inflammatory, and antioxidant responses, which contribute to reduce Aβ pathology [129].”

What the sources say

• Not checked yetcites [129] Stojakovic, 2021, Partial inhibition of mitochondrial complex I ameliorates Alzheimer’s disease pathology and cognition in APP/PS1 female mice, Commun. Biol. source

In the paper

“This report highlights also the potential of non-invasive drug delivery system based on nanoparticles that can pass the BBB and reach the brain [135].”

What the sources say

• Not checked yetcites [135] Wang, 2021, Intranasal administration of dauricine loaded on graphene oxide: Multi-target therapy for Alzheimer’s disease, Drug Deliv. source

In the paper

“It is possible to affirm that MITOL deletion triggers mitochondrial impairments and exacerbates cognitive decline in APP/PS1 mouse model with AD [131].”

What the sources say

• Not checked yetcites [131] Takeda, 2021, Mitochondrial ubiquitin ligase alleviates Alzheimer’s disease pathology via blocking the toxic amyloid-β oligomer generation, Commun. Biol. source

In the paper

“MITOL-deleted APP/PS1 mice show severe cognitive impairment, synapse alteration, and neuroinflammation mediated by excessive generation of toxic and dispersible Aβ oligomers.”

What the sources say

• Not checked yetcites [131] Takeda, 2021, Mitochondrial ubiquitin ligase alleviates Alzheimer’s disease pathology via blocking the toxic amyloid-β oligomer generation, Commun. Biol. source

In the paper

“Further, this treatment can reduce total Aβ levels triggering autophagy, one of the neuroprotective pathways essential for Aβ clearance.”

What the sources say

• Not checked yetcites [129] Stojakovic, 2021, Partial inhibition of mitochondrial complex I ameliorates Alzheimer’s disease pathology and cognition in APP/PS1 female mice, Commun. Biol. source

In the paper

“Taken together these results pointed at TUFM involvement in AD pathology by regulating BACE1 translation, apoptosis, and Tau phosphorylation, in which ROS plays an important role [130].”

What the sources say

• Not checked yetcites [130] Zhong, 2021, TUFM is involved in Alzheimer’s disease-like pathologies that are associated with ROS, FASEB J. source

In the paper

“Further, cellular ROS levels were affected by TUFM expression, and TUFM-mediated regulation of apoptosis and Tau phosphorylation is counteracted by the treatment with TEMPO, a potent antioxidant drug.”

What the sources say

• Not checked yetcites [130] Zhong, 2021, TUFM is involved in Alzheimer’s disease-like pathologies that are associated with ROS, FASEB J. source

In the paper

“Mitochondrial Tu translation elongation factor (TUFM or EF-Tu) can maintain mitochondrial respiratory chain activity and protect cell against OS.”

What the sources say

• Not checked yetcites [130] Zhong, 2021, TUFM is involved in Alzheimer’s disease-like pathologies that are associated with ROS, FASEB J. source

In the paper

“The use of minocycline, an inhibitor of microglial activation and neuroinflammation, in this model decreased the nuclear accumulation of 8-oxoG in microglial cells, and inhibited microgliosis and neuronal loss.”

What the sources say

• Not checked yetcites [125] Oka, 2021, MTH1 and OGG1 maintain a low level of 8-oxoguanine in Alzheimer’s brain, and prevent the progression of Alzheimer’s pathogenesis, Sci. Rep. source

In the paper

“They demonstrated that MTH1 and OGG1 deficiency increased 8-oxoG accumulation in nuclear and mitochondrial genomes, causing microglial activation and neuronal loss with impaired cognitive function at 4–5 months of age.”

What the sources say

• Not checked yetcites [125] Oka, 2021, MTH1 and OGG1 maintain a low level of 8-oxoguanine in Alzheimer’s brain, and prevent the progression of Alzheimer’s pathogenesis, Sci. Rep. source

In the paper

“OS and inflammation can perturbate the high-density lipoprotein (HDL) proteome, possibly playing a role in AD pathogenesis.”

What the sources say

• Not checked yetcites [147] Zimetti, 2021, Connection between the Altered HDL Antioxidant and Anti-Inflammatory Properties and the Risk to Develop Alzheimer’s Disease: A Narrative Review, Oxidative Med. Cell. Longev. source

In the paper

“NDAN patients display amyloid and tau pathology, but they resist to dementia [154].”

What the sources say

• Not checked yetcites [154] Fracassi, 2020, Oxidative Damage and Antioxidant Response in Frontal Cortex of Demented and Nondemented Individuals with Alzheimer’s Neuropathology, J. Neurosci. source

In the paper

“Salivary levels of AGE have been described to correlate with the deterioration in mini mental state examination (MMSE) score and have been suggested as potentially useful in the diagnosis of dementia [26].”

What the sources say

• Not checked yetcites [26] Choromańska, M., Klimiuk, A., Kostecka-Sochoń, P., Wilczyńska, K., Kwiatkowski, M., Okuniewska, N., Waszkiewicz, N., Zalewska, A., and Maciejczyk, M. (2017). Antioxidant Defence, Oxidative Stress and Oxidative Damage in Saliva, Plasma and Erythrocytes of Dementia Patients. Can Salivary AGE be a Marker of Dementia?. Int. J. Mol. Sci., 18. source

In the paper

“Urine contains metabolites that reflect a response to injury, including OS, occurring at high distance or carry information originated from the gut microbiome, a novel area of research in neurodegeneration and AD [138].”

What the sources say

• Not checked yetcites [138] Kurbatova, 2020, Urinary metabolic phenotyping for Alzheimer’s disease, Sci. Rep. source

In the paper

“Several redox markers were found altered in whole blood cells from AD patients, some of them (GR, GSH, GSSG, and GSSG/GSH) are already altered in MCI patients, suggesting their potential use as markers of prodromal AD.”

What the sources say

• Not checked yetcites [153] Vida, 2019, Altered Redox State in Whole Blood Cells from Patients with Mild Cognitive Impairment and Alzheimer’s Disease, J. Alzheimer’s Dis. source

In the paper

“Blood metabolic signature revealed decreased levels of specific amino acids and lipids levels in AD, and three markers of oxidative potentially predictive in demarcating AD patients from control subjects: the isoprostane-pathway derivatives 8,12-iPF-2a IV, and PGD2, and the nitro-fatty acid NO2-aLA (C18:3) [22].”

What the sources say

• Not checked yetcites [22] Peeters, 2017, Blood-based metabolic signatures in Alzheimer’s disease, Alzheimer’s Dementia: Diagn. Assess. Dis. Monit.

In the paper

“Synaptic dysfunction and synapse loss are key hallmarks of AD, present in the early stages of the disease before clinical symptoms appear [79,86,156].”

What the sources say

• Not checked yetcites [79] Selkoe, 2016, The Amyloid Hypothesis of Alzheimer’s Disease at 25 Years, EMBO Mol. Med. source
• Not checked yetcites [86] Terry, 1991, Physical basis of cognitive alterations in alzheimer’s disease: Synapse loss is the major correlate of cognitive impairment, Ann. Neurol. source
• Not checked yetcites [156] Scheff, 2014, Is synaptic loss a unique hallmark of Alzheimer’s disease?, Biochem. Pharmacol. source

In the paper

“PGC1α expression, as a key regulator of antioxidant response, was lower in AD and similar to control levels in NDAN individuals, while expression of miRNA-485, a PGC1α upstream regulator, was significantly increased in AD cortex as compared to the control and NDAN subjects [154].”

What the sources say

• Not checked yetcites [154] Fracassi, 2020, Oxidative Damage and Antioxidant Response in Frontal Cortex of Demented and Nondemented Individuals with Alzheimer’s Neuropathology, J. Neurosci. source

In the paper

“Further, they are associated with MMSE scores and seem to be useful to monitor cognitive decline in AD progression [153].”

What the sources say

• Not checked yetcites [153] Vida, 2019, Altered Redox State in Whole Blood Cells from Patients with Mild Cognitive Impairment and Alzheimer’s Disease, J. Alzheimer’s Dis. source

In the paper

“In addition, several nonenzymatic antioxidants such as vitamin C, vitamin A, vitamin E, and carotenoids were lower in the plasma of patients with AD compared with controls and are associated to increased levels of oxidative damage markers [155].”

What the sources say

• Not checked yetcites [155] Mecocci, 2002, Lymphocyte oxidative DNA damage and plasma antioxidants in Alzheimer disease, Arch. Neurol. source

In the paper

“DHA exerts its indirect antioxidant action modulating thioredoxin and glutathione pathways, and DHA supplementation is beneficial in improving cognitive function in mild AD [165].”

What the sources say

• Not checked yetcites [165] Díaz, M., Mesa-Herrera, F., and Marín, R. (2021). DHA and Its Elaborated Modulation of Antioxidant Defenses of the Brain: Implications in Aging and AD Neurodegeneration. Antioxidants, 10. source

In the paper

“Ginkgo Biloba (NCT03090516) extracts are supposed to improve mitochondrial function and brain blood flow, acting as a cognitive enhancer [163].”

What the sources say

• Not checked yetcites [163] Cummings, 2021, Alzheimer’s disease drug development pipeline: 2021, Alzheimer’s Dement Transl. Res. Clin. Interv. source

In the paper

“Of the 18 agents in phase 3 classified as disease-modifying treatments, three have OS as mechanism of action, two have metabolism/bioenergetic, two have antioxidant properties, and among the three agents acting on synaptic plasticity/neuroprotection, Azeliragon is also meant to ameliorate OS (Table 2).”

What the sources say

• Not checked yetcites [163] Cummings, 2021, Alzheimer’s disease drug development pipeline: 2021, Alzheimer’s Dement Transl. Res. Clin. Interv. source

In the paper

“RAGE can also bind amyloid and is upregulated in astrocytes and microglia of AD patients [47].”

What the sources say

• Not checked yetcites [47] Lue, 2001, Involvement of Microglial Receptor for Advanced Glycation Endproducts (RAGE) in Alzheimer’s Disease: Identification of a Cellular Activation Mechanism, Exp. Neurol. source

In the paper

“The therapeutic purpose of the treatment with this compound is its potential to correct a number of metabolic and synaptic abnormalities, as this receptor has been shown to restore cellular homeostasis and synaptic plasticity when activated by targeting mitochondrial dysfunction and associated OS, protein misfolding, proteostasis, and associated autophagy, and neuroinflammation [164].”

What the sources say

• Not checked yetcites [164] Kaufmann, 2019, ANAVEX®2-73 (blarcamesine), a Sigma-1 receptor agonist, ameliorates neurologic impairments in a mouse model of Rett syndrome, Pharmacol. Biochem. Behav. source

In the paper

“Besides, oxidative damage may be linked to the genetic risk of AD, and in this view more relevant in patients carrying the APOE ε4 allele [169].”

What the sources say

• Not checked yetcites [169] Zabel, 2017, Markers of oxidative damage to lipids, nucleic acids and proteins and antioxidant enzymes activities in Alzheimer’s disease brain: A meta-analysis in human pathological specimens, Free. Radic. Biol. Med. source

In the paper

“Concerning the treatment of patients with antioxidative compounds, clearly any supplementation can be considered curative, but, in the context of a multifactorial disease, it may help to reduce or limit pathogenic events eventually leading to neurodegeneration.”

In the paper

“The study of accumulation of the products of oxidative damage in the brain and specimens has surely shed light on the early events of AD pathology and has contributed to the knowledge of AD pathogenesis.”

In the paper

“Glucose metabolism amelioration in CNS is supposed to improve the cognitive decline of aMCI patients or prevent the cognitive decline in obese people [163,167].”

What the sources say

• Not checked yetcites [163] Cummings, 2021, Alzheimer’s disease drug development pipeline: 2021, Alzheimer’s Dement Transl. Res. Clin. Interv. source
• Not checked yetcites [167] Correia, 2011, Insulin-resistant brain state: The culprit in sporadic Alzheimer’s disease?, Ageing Res. Rev. source

In the paper

“On the other hand, OS is a state which can be determined by aging and other comorbidities, representing a risk factor for AD in health people or a progression factor for the MCI patients.”

In the paper

“Another molecule in Phase 3 is Azeliragon (NTC03980730), an inhibitor of RAGE that can be administered orally [163].”

What the sources say

• Not checked yetcites [163] Cummings, 2021, Alzheimer’s disease drug development pipeline: 2021, Alzheimer’s Dement Transl. Res. Clin. Interv. source

In the paper

“As previously discussed in this review, AGEs through the binding to the receptor, can produce ROS and be involved in neurodegeneration [42].”

What the sources say

• Not checked yetcites [42] Rungratanawanich, 2021, Advanced glycation end products (AGEs) and other adducts in aging-related diseases and alcohol-mediated tissue injury, Exp. Mol. Med. source

In the paper

“Blarcamesine or ANAVEX2-73 (NTC03790709) is a chemical compound known as an agonist of the sigma 1 receptor [164].”

What the sources say

• Not checked yetcites [164] Kaufmann, 2019, ANAVEX®2-73 (blarcamesine), a Sigma-1 receptor agonist, ameliorates neurologic impairments in a mouse model of Rett syndrome, Pharmacol. Biochem. Behav. source

In the paper

“Despite the failure of studies on oxidative damage products in AD to reveal, till now, one or more reliable marker, oxidative damage can be localized to mitochondria in AD brain and ROS may act as second messenger, initiating a downstream signaling pathway to face up the alteration in the redox balance [169].”

What the sources say

• Not checked yetcites [169] Zabel, 2017, Markers of oxidative damage to lipids, nucleic acids and proteins and antioxidant enzymes activities in Alzheimer’s disease brain: A meta-analysis in human pathological specimens, Free. Radic. Biol. Med. source