The DOI matches its Crossref record; 216 of the 220 references it cites were found in a registry or an index; none of the 182 sources its claims cite is checked for support yet.
Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease
Open accessAbstract
The aberrant accumulation of aggregated β-amyloid peptides (Aβ) as plaques is a hallmark of Alzheimer’s disease (AD) neuropathology and reduction of Aβ has become a leading direction of emerging experimental therapies for the disease. The mechanism(s) whereby Aβ is involved in the pathophysiology of the disease remain(s) poorly understood. Initially fibrils, and subsequently oligomers of extracellular Aβ have been viewed as the most important pathogenic form of Aβ in AD. More recently, the intraneuronal accumulation of Aβ has been described in the brain, although technical considerations and its relevance in AD have made this a controversial topic. Here, we review the emerging evidence linking intraneuronal Aβ accumulation to the development of synaptic pathology and plaques in AD, and discuss the implications of intraneuronal β-amyloid for AD pathology, biology, diagnosis and therapy.
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TL;DR
This review argues that intraneuronal Aβ42 accumulation, particularly in endosomes/multivesicular bodies of distal neurites and synapses, precedes plaques and is linked to synaptic pathology in Alzheimer’s disease. It proposes that this intracellular pool, rather than solely extracellular plaques, may be the critical Aβ species for pathogenesis, diagnosis, and therapy.
Key findings
- Intraneuronal Aβ42 accumulates in AD-vulnerable neurons and Down syndrome brains before plaques; immuno-EM localizes Aβ42 primarily to endosomal multivesicular bodies in distal neurites and pre-/post-synaptic compartments, and higher-molecular-weight Aβ42 oligomers are associated with neuritic degeneration even prior to plaques.
- FAD mutations in APP/presenilin increase the Aβ42 to Aβ40 ratio and can relatively increase intracellular versus secreted Aβ; soluble brain Aβ42 correlates best with cognitive decline, while CSF Aβ42 declines early.
- Intraneuronal Aβ42 may link Aβ and tau pathology: neuron cell bodies with early intraneuronal Aβ42 are those that develop NFTs, and phospho-tau co-localizes with Aβ42 in dystrophic neurites around plaques in transgenic mouse and human AD.
- Therapeutic implications: reducing intraneuronal rather than extracellular Aβ correlated with synaptic improvement; Aβ antibodies can reduce intraneuronal Aβ in vivo/in vitro, suggesting plaque Aβ may sequester antibodies and limit efficacy.
Methods
- Narrative review; no primary experimental design. Synthesizes published human postmortem AD/Down syndrome brain studies, AD transgenic mouse/rat models, cultured primary neurons, and biochemical/imaging/CSF studies.
- Main analysis is qualitative integration of immuno-histochemistry, immuno-electron microscopy, biochemical Aβ assays, and transgenic model evidence to build a hypothesis of intraneuronal Aβ pathogenesis.
Limitations
- Paper states detection is controversial and technically challenging: Aβ/APP antibodies cross-react with APP/βCTFs; C-terminal Aβ42 antibodies detect monomers poorly after oligomerization; N-terminal Aβ1-x antibodies also detect βCTFs and miss N-truncated Aβ42; ELISA/immunoprecipitation can underestimate aggregated Aβ.
- Paper states intraneuronal Aβ42 labeling appears to decline with advancing plaque pathology, and it remains unclear whether this reflects epitope loss, synaptic redistribution, degradation, or irrelevance; human brain variability, postmortem interval, fixation, and agonal state affect interpretation.
- Evident: as a narrative review, it lacks systematic search/quantitative synthesis and does not provide new primary data; many proposed mechanisms remain hypotheses.
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In the paper
“FAD mutations actually cause a relatively greater increase in intracellular compared to secreted Aβ ([202], and unpublished observations).”
§ Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease > Concerns about intraneuronal Aβ accumulation in AD > Familial AD mutations
What the sources say
- Not checked yetcites [202] Wild-Bode C, Yamazaki T, Capell A et al (1997) Intracellular generation and accumulation of amyloid beta-peptide terminating at amino acid 42. J Biol Chem 272:16085–16088 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“other biochemical Aβ detection methods, such as immunoprecipitation, can vastly underestimate total Aβ levels, since spiking of samples with a defined amount of Aβ1-42 reveals that only a very small fraction of the added Aβ can subsequently be detected (personal observations).”
§ Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease > Concerns about intraneuronal Aβ accumulation in AD > Biochemical evidence on intraneuronal Aβ accumulation
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In the paper
“In addition, dementia pugilistica that develops in professional boxers [31], while characterized by significant tauopathy and comparably less amyloid pathology, limited mainly to diffuse plaques [27], also shows considerable intraneuronal Aβ42 (Fig. 4c).”
§ Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease > Pathology > Head trauma and intraneuronal Aβ
What the sources say
- Not checked yetcites [31] Corsellis JA, Bruton CJ, Freeman-Browne D (1973) The aftermath of boxing. Psychol Med 3:270–303 source
- Not checked yetcites [27] Clinton J, Ambler MW, Roberts GW (1991) Post-traumatic Alzheimer’s disease: preponderance of a single plaque type. Neuropathol Appl Neurobiol 17:69–74 source
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We have observed marked up-regulation of intraneuronal Aβ42 in surrounding neurites and neuron cell bodies near needle track injuries in the rodent brains 48 to 72 hours following brain injury (Fig. 4a).”
§ Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease > Pathology > Head trauma and intraneuronal Aβ
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“By immuno-EM these increases in Aβ42 occurred predominantly in endosomes (Fig. 4b).”
§ Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease > Pathology > Head trauma and intraneuronal Aβ
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In the paper
“The aberrant accumulation of aggregated β-amyloid peptides (Aβ) as plaques is a hallmark of Alzheimer’s disease (AD) neuropathology”
- Also stated in: § Introduction · plain
“The anatomically selective and differential accumulation of Aβ plaques and neurofibrillary tangles (NFTs) are neuropathological hallmarks of AD [193, 207].”
§ Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease > Abstract
What the sources say
- Not checked yetcites [193] Thal DR, Del Tredici K, Braak H (2004) Neurodegeneration in normal brain aging and disease. Sci Aging Knowl Environ 9:pe26 source
- Not checked yetcites [207] WorkingGroup (1997) Consensus recommendations for the postmortem diagnosis of Alzheimer’s disease. The National Institute on aging, and Reagan Institute Working Group on Diagnostic Criteria for the Neuropathological Assessment of Alzheimer’s Disease. Neurobiol Aging 18:S1–S2
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § Introduction · plain
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In the paper
“research studies have reported that loss of synaptic markers, specifically of the pre-synaptic protein synaptophysin, is the best brain correlate of cognitive decline in AD [40, 42, 168, 184, 192].”
§ Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease > Introduction
What the sources say
- Not checked yetcites [40] Davies CA, Mann DM, Sumpter PQ, Yates PO (1987) A quantitative morphometric analysis of the neuronal and synaptic content of the frontal and temporal cortex in patients with Alzheimer’s disease. J Neurol Sci 78:151–164 source
- Not checked yetcites [42] DeKosky ST, Scheff SW (1990) Synapse loss in frontal cortex biopsies in Alzheimer’s disease: correlation with cognitive severity. Ann Neurol 27:457–464 source
- Not checked yetcites [168] Selkoe DJ (2002) Alzheimer’s disease is a synaptic failure. Science 298:789–791 source
- Not checked yetcites [184] Sze CI, Troncoso JC, Kawas C, Mouton P, Price DL, Martin LJ (1997) Loss of the presynaptic vesicle protein synaptophysin in hippocampus correlates with cognitive decline in Alzheimer disease. J Neuropathol Exp Neurol 56:933–944 source
- Not checked yetcites [192] Terry RD, Masliah E, Salmon DP et al (1991) Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol 30:572–580 source
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA 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
“Current evidence argues against another APP cleavage product being more important than specifically the Aβ42 isoform in AD.”
§ Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease > Central role of Aβ in Alzheimer’s disease
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIn the paper
“the earliest Aβ42 in plaques appears to be N-truncated [98].”
§ Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease > Central role of Aβ in Alzheimer’s disease
What the sources say
- Not checked yetcites [98] Lemere CA, Blusztajn JK, Yamaguchi H, Wisniewski T, Saido TC, Selkoe DJ (1996) Sequence of deposition of heterogeneous amyloid beta-peptides and APO E in Down syndrome: implications for initial events in amyloid plaque formation. Neurobiol Dis 3:16–32 source
Strength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIn the paper
“the slightly longer Aβ42 species that is specifically linked with FAD is also the first Aβ species deposited in cerebral plaques [82].”
§ Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease > Central role of Aβ in Alzheimer’s disease
What the sources say
- Not checked yetcites [82] Iwatsubo T, Odaka A, Suzuki N, Mizusawa H, Nukina N, Ihara Y (1994) Visualization of A beta 42(43) and A beta 40 in senile plaques with end-specific A beta monoclonals: evidence that an initially deposited species is A beta 42(43). Neuron 13:45–53 source
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
- It may state two separate claims as one. 40
- Probably not a substantial claim. 9
None of the sources cited for this claim have been checked yet.
In the paper
“progressive N-truncation increases the propensity of aggregation [146, 165] and toxicity [23]”
§ Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease > Central role of Aβ in Alzheimer’s disease
What the sources say
- Not checked yetcites [146] Pike CJ, Overman MJ, Cotman CW (1995) Amino-terminal deletions enhance aggregation of beta-amyloid peptides in vitro. J Biol Chem 270:23895–23898 source
- Not checked yetcites [165] Schlenzig D, Manhart S, Cinar Y et al (2009) Pyroglutamate formation influences solubility and amyloidogenicity of amyloid peptides. Biochemistry 48:7072–7078 source
- Not checked yetcites [23] Casas C, Sergeant N, Itier JM et al (2004) Massive CA1/2 neuronal loss with intraneuronal and N-terminal truncated Abeta42 accumulation in a novel Alzheimer transgenic model. Am J Pathol 165:1289–1300 source
Strength:boosted· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Experimental therapies, such as Aβ immunotherapy [8, 53, 138, 164, 178], were not only shown to reduce cerebral Aβ, but even more importantly, to improve behavior in transgenic mouse models of AD-like cerebral β-amyloidosis.”
§ Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease > Central role of Aβ in Alzheimer’s disease
What the sources say
- Not checked yetcites [8] Bard F, Cannon C, Barbour R et al (2000) 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 source
- Not checked yetcites [53] Golde TE, Das P, Levites Y (2009) Quantitative and mechanistic studies of Abeta immunotherapy. CNS Neurol Disord Drug Targets 8:31–49 source
- Not checked yetcites [138] Oddo S, Billings L, Kesslak JP, Cribbs DH, LaFerla FM (2004) Abeta immunotherapy leads to clearance of early, but not late, hyperphosphorylated tau aggregates via the proteasome. Neuron 43:321–332 source
- Not checked yetcites [164] Schenk D, Barbour R, Dunn W et al (1999) Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 400:173–177 source
- Not checked yetcites [178] Solomon B (2007) Clinical immunologic approaches for the treatment of Alzheimer’s disease. Expert Opin Investig Drugs 16:819–828 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“In 1993 the first biological paper appeared on the presence of Aβ within cells [201].”
§ Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease > Intraneuronal Aβ in Alzheimer’s disease
What the sources say
- Not checked yetcites [201] Wertkin AM, Turner RS, Pleasure SJ et al (1993) Human neurons derived from a teratocarcinoma cell line express solely the 695-amino acid amyloid precursor protein and produce intracellular beta-amyloid or A4 peptides. Proc Natl Acad Sci USA 90:9513–9517 source
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
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
“Current data suggest a hierarchy in the development of AD with aging, that emerging evidence increasingly supports begins with declining levels of Aβ42 in cerebrospinal fluid (CSF) and accumulation of intraneuronal Aβ42”
§ Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease > Central role of Aβ in Alzheimer’s disease
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
“these pan-Aβ antibodies directed at the Aβ domain detect not only Aβ peptides but also the normally much more abundant full-length APP, and additionally, other Aβ-containing APP fragments such as β-secretase cleaved APP βCTFs”
§ Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease > Intraneuronal Aβ in Alzheimer’s disease
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
“An intracellular environment should be more favorable for allowing Aβ aggregation, since intracellular organelles can have a lower pH, higher metal ion concentrations and provide a limited space.”
§ Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease > Intraneuronal Aβ in Alzheimer’s disease
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✗ Based: failsProbably not a substantial claim. The paper may give no reason why it holds.
In the paper
“This publication described prominent early Aβ42 labeling of AD vulnerable neuron cell bodies, but not their nuclei, in pre-plaque Down syndrome brains and also non-Down syndrome brains, particularly those with early AD neuropathological changes.”
§ Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease > Intraneuronal Aβ in Alzheimer’s disease > Intraneuronal Aβ in brain by light microscopy
What the sources say
- Not checked yetcites [60] Gouras GK, Tsai J, Naslund J et al (2000) Intraneuronal Abeta42 accumulation in human brain. Am J Pathol 156:15–20 source
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Thus, while aberrant Aβ42 accumulation begins in endosomes, mitochondrial Aβ may be a critical contributor in the pathological cascade leading to neuronal dysfunction and pathology in AD [33, 103, 149].”
§ Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease > Concerns about intraneuronal Aβ accumulation in AD > Aβ in mitochondria
What the sources say
- Not checked yetcites [33] Chen X, Yan SD (2006) Mitochondrial Abeta: a potential cause of metabolic dysfunction in Alzheimer’s disease. IUBMB Life 58:686–694 source
- Not checked yetcites [103] Lin MT, Beal MF (2006) Alzheimer’s APP mangles mitochondria. Nat Med 12:1241–1243 source
- Not checked yetcites [149] Reddy PH (2008) Mitochondrial medicine for aging and neurodegenerative diseases. Neuromolecular Med 10:291–315 source
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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
“Detection of intraneuronal Aβ is even more challenging in human brain, where in contrast to AD transgenic mice, APP is not over-expressed and FAD mutations that elevate Aβ42 are rare.”
§ Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease > Concerns about intraneuronal Aβ accumulation in AD > Aβ antibody specificity and immunostaining
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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
“Moreover, intraneuronal Aβ is best appreciated at early stages of pathology in AD transgenic mouse and human AD brains, while postmortem human AD brains are more often examined at end stages of disease.”
§ Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease > Concerns about intraneuronal Aβ accumulation in AD > Aβ antibody specificity and immunostaining
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“a recent study indicated that cognitive decline in AD tracked best with the membranous pool of Aβ42 in brain tissue from human AD [180]; it was concluded that this membrane-associated Aβ42 was cell associated and reflected intraneuronal Aβ42.”
§ Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease > Concerns about intraneuronal Aβ accumulation in AD > Biochemical evidence on intraneuronal Aβ accumulation
What the sources say
- Not checked yetcites [180] Steinerman JR, Irizarry M, Scarmeas N et al (2008) Distinct pools of beta-amyloid in Alzheimer disease-affected brain: a clinicopathologic study. Arch Neurol 65:906–912 source
Strength:hedged· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“C-terminal specific Aβ42 antibodies typically are best at detecting Aβ42 monomers, and have minimal reactivity against oligomers larger than trimers [187].”
§ Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease > Concerns about intraneuronal Aβ accumulation in AD > Aβ antibody specificity and immunostaining
What the sources say
- Not checked yetcites [187] Takahashi RH, Almeida CG, Kearney PF et al (2004) Oligomerization of Alzheimer’s beta-amyloid within processes and synapses of cultured neurons and brain. J Neurosci 24:3592–3599 source
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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
“Although the presence of intraneuronal Aβ accumulation has now been widely detected in brains of human Down syndrome and AD, and transgenic models of AD, skepticism persists.”
§ Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease > Concerns about intraneuronal Aβ accumulation in AD > Aβ antibody specificity and immunostaining
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Studies have increasingly differentiated between soluble and insoluble pools of Aβ within the brain, where it is the increase in the soluble pool of Aβ42 that tracks best with cognitive decline in AD [108, 118, 130].”
§ Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease > Concerns about intraneuronal Aβ accumulation in AD > Biochemical evidence on intraneuronal Aβ accumulation
What the sources say
- Not checked yetcites [108] Lue LF, Kuo YM, Roher AE et al (1999) Soluble amyloid beta peptide concentration as a predictor of synaptic change in Alzheimer’s disease. Am J Pathol 155:853–862 source
- Not checked yetcites [118] McLean CA, Cherny RA, Fraser FW et al (1999) Soluble pool of Abeta amyloid as a determinant of severity of neurodegeneration in Alzheimer’s disease. Ann Neurol 46:860–866 source
- Not checked yetcites [130] Naslund J, Haroutunian V, Mohs R et al (2000) Correlation between elevated levels of amyloid beta-peptide in the brain and cognitive decline. JAMA 283:1571–1577 source
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Postmortem interval, pre-treatments, counter-stains, fixation and post-fixation, detergent, and blocking solutions, all can influence interpretation of immuno-histochemistry, and also that of intraneuronal Aβ [34, 39].”
§ Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease > Concerns about intraneuronal Aβ accumulation in AD > Aβ antibody specificity and immunostaining
What the sources say
- Not checked yetcites [34] Christensen DZ, Bayer TA, Wirths O (2009) Formic acid is essential for immunohistochemical detection of aggregated intraneuronal Abeta peptides in mouse models of Alzheimer’s disease. Brain Res 1301:116–125 source
- Not checked yetcites [39] D’Andrea MR, Reiser PA, Polkovitch DA et al (2003) The use of formic acid to embellish amyloid plaque detection in Alzheimer’s disease tissues misguides key observations. Neurosci Lett 342:114–118 source
Strength:plain· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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
“it is not common knowledge that commercial antibodies can change. Particularly polyclonal antibodies can have batch to batch variations that can significantly affect interpretation.”
§ Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease > Concerns about intraneuronal Aβ accumulation in AD > Aβ antibody specificity and immunostaining
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✗ Based: failsProbably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds. It may state two separate claims as one.
In the paper
“When the same amounts of Aβ1-42 were incubated over time, levels of Aβ42 assayed by a standard non-denaturing ELISA appeared to decline as a function of time, while denaturing Western blotting indicated that levels were actually unchanged; this occurred because ongoing Aβ aggregation progressively blocked access of the Aβ42 antibody in the ELISA.”
§ Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease > Concerns about intraneuronal Aβ accumulation in AD > Biochemical evidence on intraneuronal Aβ accumulation
What the sources say
- Not checked yetcites [181] Stenh C, Englund H, Lord A et al (2005) Amyloid-beta oligomers are inefficiently measured by enzyme-linked immunosorbent assay. Ann Neurol 58:147–150 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“It should be noted that there also is variability in the degree of intraneuronal Aβ labeling [60], which is more pronounced in human compared to AD transgenic mouse brains.”
§ Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease > Concerns about intraneuronal Aβ accumulation in AD > Aβ antibody specificity and immunostaining
What the sources say
- Not checked yetcites [60] Gouras GK, Tsai J, Naslund J et al (2000) Intraneuronal Abeta42 accumulation in human brain. Am J Pathol 156:15–20 source
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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
“One possible explanation for this concern is that Aβ aggregation leads to conformational changes and thereby the reduced ability of Aβ antibodies in detecting their antigens.”
§ Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease > Concerns about intraneuronal Aβ accumulation in AD > Relevance of intraneuronal Aβ to AD pathogenesis
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Since the triple transgenic mouse expressing mutant APP, PS1 and tau develops early Aβ accumulation in CA1 hippocampal neurons and later tau paired helical filaments [140], the stratum lacunosum-moleculare (SLM) of hippocampus containing the CA1 distal apical dendrites was selectively examined by immuno-EM.”
§ Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease > Pathology > Pathological relation between Aβ, tau and synapses in Alzheimer’s disease
What the sources say
- Not checked yetcites [140] Oddo S, Caccamo A, Shepherd JD et al (2003) Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron 39:409–421 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“An example of this is the early accumulation of Aβ42 within layer II neuron cell bodies of the entorhinal cortex and early plaques at their axonal terminal fields in the outer molecular layer of the dentate in the hippocampus [60].”
§ Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease > Pathology > Pathological relation between Aβ, tau and synapses in Alzheimer’s disease
What the sources say
- Not checked yetcites [60] Gouras GK, Tsai J, Naslund J et al (2000) Intraneuronal Abeta42 accumulation in human brain. Am J Pathol 156:15–20 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“a recent E693Delta mutation in APP was reported to be associated with an AD clinical phenotype in the absence of plaques; cells harboring this mutation were shown to have reduced Aβ secretion and increased intracellular Aβ accumulation and oligomerization [134].”
§ Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease > Concerns about intraneuronal Aβ accumulation in AD > Familial AD mutations
What the sources say
- Not checked yetcites [134] Nishitsuji K, Tomiyama T, Ishibashi K et al (2009) The E693Delta mutation in amyloid precursor protein increases intracellular accumulation of amyloid beta oligomers and causes endoplasmic reticulum stress-induced apoptosis in cultured cells. Am J Pathol 174:957–969 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“In one study, Aβ-induced abnormalities in MVB endocytic sorting were demonstrated in APP mutant neurons, which appeared to be due to impairment of the ubiquitin proteasome system (UPS; [2]).”
§ Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease > Concerns about intraneuronal Aβ accumulation in AD > Many questions remain for the role of intraneuronal Aβ in Alzheimer’s disease
What the sources say
- Not checked yetcites [2] Almeida CG, Takahashi RH, Gouras GK (2006) Beta-amyloid accumulation impairs multivesicular body sorting by inhibiting the ubiquitin-proteasome system. J Neurosci 26:4277–4288 source
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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
“The lack of correlation between Aβ plaques and cognitive decline in AD may relate to person-to-person differences in the ability of inflammatory cells to effectively remove Aβ plaques from the brain.”
§ Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease > Implications of intraneuronal Aβ for Alzheimer’s disease
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✗ Based: failsProbably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“Specifically, immuno-histochemical data support that neuron cell bodies with early intraneuronal Aβ42 accumulation are those that go on to develop NFTs [60, 140], while their terminal fields are sites of early plaque pathology.”
§ Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease > Pathology > Pathological relation between Aβ, tau and synapses in Alzheimer’s disease
What the sources say
- Not checked yetcites [60] Gouras GK, Tsai J, Naslund J et al (2000) Intraneuronal Abeta42 accumulation in human brain. Am J Pathol 156:15–20 source
- Not checked yetcites [140] Oddo S, Caccamo A, Shepherd JD et al (2003) Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron 39:409–421 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Remarkably, the SLM showed not only prominent early Aβ42 increases but also the earliest labeling with antibodies against phospho-tau, such as the well-established antibody AT8.”
§ Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease > Pathology > Pathological relation between Aβ, tau and synapses in Alzheimer’s disease
What the sources say
- Not checked yetcites [186] Takahashi RH, Capetillo-Zarate E, Lin MT, Milner TA, Gouras GK (2008) Co-occurrence of Alzheimer’s disease beta-amyloid and tau pathologies at synapses. Neurobiol Aging. doi: 101016/jneurobiolaging200807021
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“the most marked accumulation of intraneuronal Aβ42 occurs in distal neurites and synaptic compartments as determined by immuno-EM [188] that cannot be visualized effectively by light or standard immuno-fluorescence microscopy.”
§ Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease > Concerns about intraneuronal Aβ accumulation in AD > Relevance of intraneuronal Aβ to AD pathogenesis
What the sources say
- Not checked yetcites [188] Takahashi RH, Milner TA, Li F et al (2002) Intraneuronal Alzheimer abeta42 accumulates in multivesicular bodies and is associated with synaptic pathology. Am J Pathol 161:1869–1879 source
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“Indirect support for synapse-specific Aβ generation also comes from PS1 conditional knockout mice, which showed aberrant accumulation of APP βCTFs in distal axons/pre-synaptic compartments [162] and also some anatomically selective accumulation in distal dendrites/post-synaptic compartments (personal observations).”
§ Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease > Pathology > Additional evidence for synapses as sites of Alzheimer’s disease pathology
What the sources say
- Not checked yetcites [162] Saura CA, Chen G, Malkani S et al (2005) Conditional inactivation of presenilin 1 prevents amyloid accumulation and temporarily rescues contextual and spatial working memory impairments in amyloid precursor protein transgenic mice. J Neurosci 25:6755–6764 source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt 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 data build on previous studies to provide an early temporal and spatial relationship of the main constituents of the two neuropathological hallmarks of AD and thereby also link them with synapse pathology in AD.”
§ Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease > Pathology > Pathological relation between Aβ, tau and synapses in Alzheimer’s disease
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Synapses have long been viewed as critical sites of AD pathology [6, 28, 112, 119, 168] and diverse evidence had supported that synapses are major sites of Aβ pathology and also generation.”
§ Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease > Pathology > Additional evidence for synapses as sites of Alzheimer’s disease pathology
What the sources say
- Not checked yetcites [6] Arendt T (2009) Synaptic degeneration in Alzheimer’s disease. Acta Neuropathol 118:167–179 source
- Not checked yetcites [28] Coleman PD, Yao PJ (2003) Synaptic slaughter in Alzheimer’s disease. Neurobiol Aging 24:1023–1027 source
- Not checked yetcites [112] Masliah E, Crews L, Hansen L (2006) Synaptic remodeling during aging and in Alzheimer’s disease. J Alzheimers Dis 9:91–99 source
- Not checked yetcites [119] Mesulam MM (1999) Neuroplasticity failure in Alzheimer’s disease: bridging the gap between plaques and tangles. Neuron 24:521–529 source
- Not checked yetcites [168] Selkoe DJ (2002) Alzheimer’s disease is a synaptic failure. Science 298:789–791 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
“Overall, emerging work on intraneuronal Aβ is most consistent with the scenario of aging, and other genetic and environmental risk factors, such as apoEε4 and head injury, respectively, leading to up-regulation and then oligomerization of intraneuronal Aβ42 in distal neurites and synapses, which then leads directly to destruction of neurites and synapses from within (Fig. 3).”
§ Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease > Pathology > Additional evidence for synapses as sites of Alzheimer’s disease pathology
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
“In particular dense core plaques appear to be derived from neuron cell bodies, although even here it is possible that dendritic Aβ42 accumulations are the inciting event.”
§ Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease > Pathology > Questions for intraneuronal Aβ in Alzheimer’s disease neuropathology
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✗ Based: failsProbably not a substantial claim. The paper’s conclusions may not depend on it. The paper may give no reason why it holds.
None of the sources cited for this claim have been checked yet.
In the paper
“Many in vitro and in vivo studies have shown that exogenous application of Aβ alters synaptic plasticity [170, 198] and important synaptic proteins [3, 79, 177], although how precisely this occurs remains unclear.”
§ Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease > Biology
What the sources say
- Not checked yetcites [170] Shankar GM, Li S, Mehta TH et al (2008) Amyloid-beta protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and memory. Nat Med 14:837–842 source
- Not checked yetcites [198] Walsh DM, Klyubin I, Fadeeva JV et al (2002) Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo. Nature 416:535–539 source
- Not checked yetcites [3] Almeida CG, Tampellini D, Takahashi RH et al (2005) Beta-amyloid accumulation in APP mutant neurons reduces PSD-95 and GluR1 in synapses. Neurobiol Dis 20:187–198 source
- Not checked yetcites [79] Hsieh H, Boehm J, Sato C et al (2006) AMPAR removal underlies Abeta-induced synaptic depression and dendritic spine loss. Neuron 52:831–843 source
- Not checked yetcites [177] Snyder EM, Nong Y, Almeida CG et al (2005) Regulation of NMDA receptor trafficking by amyloid-beta. Nat Neurosci 8:1051–1058 source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“At first this seems difficult to reconcile with recent data showing that patients in coma have marked reductions in extracellular Aβ42, which rises and falls with cognitive improvement and decline, respectively [16].”
§ Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease > Pathology > Head trauma and intraneuronal Aβ
What the sources say
- Not checked yetcites [16] Brody DL, Magnoni S, Schwetye KE et al (2008) Amyloid-beta dynamics correlate with neurological status in the injured human brain. Science 321:1221–1224 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. 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
“Degree of intraneuronal Aβ42 might tightly correlate with synaptic dysfunction, whereas synapse-independent factors might dissociate plaque burden from cognitive decline, for example, genetic heterogeneity may exist in the ability of inflammatory cells to remove plaques.”
§ Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease > Pathology > Additional evidence for synapses as sites of Alzheimer’s disease pathology
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✗ Based: failsProbably not a substantial claim. The paper may give no reason why it holds. It may state two separate claims as one.
In the paper
“That this pathological accumulation is most prominent in distal neurites and synapses of AD transgenic mice provided the first direct association between Aβ and synapse pathologies in the brain [188].”
§ Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease > Biology
What the sources say
- Not checked yetcites [188] Takahashi RH, Milner TA, Li F et al (2002) Intraneuronal Alzheimer abeta42 accumulates in multivesicular bodies and is associated with synaptic pathology. Am J Pathol 161:1869–1879 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Remarkably, it was demonstrated that Aβ antibodies can reduce the intraneuronal pool of Aβ in vivo [138] and in vitro [189], which for the latter was shown to required Aβ antibody internalization.”
§ Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease > Therapy
What the sources say
- Not checked yetcites [138] Oddo S, Billings L, Kesslak JP, Cribbs DH, LaFerla FM (2004) Abeta immunotherapy leads to clearance of early, but not late, hyperphosphorylated tau aggregates via the proteasome. Neuron 43:321–332 source
- Not checked yetcites [189] Tampellini D, Magrane J, Takahashi RH et al (2007) Internalized antibodies to the Abeta domain of APP reduce neuronal Abeta and protect against synaptic alterations. J Biol Chem 282:18895–18906 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Another explanation for the potential Aβ/synaptic activity paradox is that sites of high cerebral activity, in the default system, are indeed sites of early AD neuropathology [18, 179], but not necessarily because of increased Aβ secretion.”
§ Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease > Therapy > Role of synaptic activity in Alzheimer’s disease
What the sources say
- Not checked yetcites [18] Buckner RL, Snyder AZ, Shannon BJ et al (2005) Molecular, structural, and functional characterization of Alzheimer’s disease: evidence for a relationship between default activity, amyloid, and memory. J Neurosci 25:7709–7717 source
- Not checked yetcites [179] Sperling RA, Laviolette PS, O’Keefe K et al (2009) Amyloid deposition is associated with impaired default network function in older persons without dementia. Neuron 63:178–188 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Furthermore, Aβ secretion is also increased with cognitive activity, since patients in coma showed elevations in Aβ with cognitive improvement; a subsequent decline in cognitive function correlated with decline in interstitial/extracellular Aβ levels [16].”
§ Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease > Therapy > Role of synaptic activity in Alzheimer’s disease
What the sources say
- Not checked yetcites [16] Brody DL, Magnoni S, Schwetye KE et al (2008) Amyloid-beta dynamics correlate with neurological status in the injured human brain. Science 321:1221–1224 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Furthermore, functional brain imaging shows reduced resting brain activity in subjects with AD, and even in genetically at-risk subjects decades prior to predicted cognitive symptoms [150].”
§ Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease > Therapy > Role of synaptic activity in Alzheimer’s disease
What the sources say
- Not checked yetcites [150] Reiman EM, Chen K, Alexander GE et al (2004) Functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer’s dementia. Proc Natl Acad Sci USA 101:284–289 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Work in the 1990s had shown that extracellular Aβ1-42 led to marked up-regulation of endogenously generated Aβ42 [51, 211], which also occurs in neurons [190].”
§ Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease > Biology
What the sources say
- Not checked yetcites [51] Glabe C (2001) Intracellular mechanisms of amyloid accumulation and pathogenesis in Alzheimer’s disease. J Mol Neurosci 17:137–145 source
- Not checked yetcites [211] Yang AJ, Chandswangbhuvana D, Shu T, Henschen A, Glabe CG (1999) Intracellular accumulation of insoluble, newly synthesized abeta n-42 in amyloid precursor protein-transfected cells that have been treated with Abeta1-42. J Biol Chem 274:20650–20656 source
- Not checked yetcites [190] Tampellini D, Rahman N, Gallo EF et al (2009) Synaptic activity reduces intraneuronal Abeta, promotes APP transport to synapses, and protects against Abeta-related synaptic alterations. J Neurosci 29:9704–9713 source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“Recently, additional evidence pointed to the importance of amyloidogenic processing of APP, and therefore potentially intraneuronal Aβ, in extracellular Aβ-induced synapse dysfunction [190].”
§ Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease > Biology
What the sources say
- Not checked yetcites [190] Tampellini D, Rahman N, Gallo EF et al (2009) Synaptic activity reduces intraneuronal Abeta, promotes APP transport to synapses, and protects against Abeta-related synaptic alterations. J Neurosci 29:9704–9713 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“The protease shown to most efficiently degrade Aβ, neprilysin [81], was reported to be critical in synaptic activity-induced intraneuronal Aβ42 reduction [190].”
§ Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease > Therapy > Role of synaptic activity in Alzheimer’s disease
What the sources say
- Not checked yetcites [81] Iwata N, Tsubuki S, Takaki Y et al (2000) Identification of the major Abeta1-42-degrading catabolic pathway in brain parenchyma: suppression leads to biochemical and pathological deposition. Nat Med 6:143–150 source
- Not checked yetcites [190] Tampellini D, Rahman N, Gallo EF et al (2009) Synaptic activity reduces intraneuronal Abeta, promotes APP transport to synapses, and protects against Abeta-related synaptic alterations. J Neurosci 29:9704–9713 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt 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
“Similar to tau aggregation developing within neurons but then as ghost tangles no longer within living neurons, Aβ accumulation also begins intracellularly and ends up extracellular following neuritic degeneration.”
§ Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease > Conclusion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes? Based: unclearIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Given that neprilysin localizes to synapses and declines with aging [20, 50], declining neprilysin may be important in the age-related intraneuronal accumulation of Aβ in synapses.”
§ Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease > Therapy > Role of synaptic activity in Alzheimer’s disease
What the sources say
- Not checked yetcites [20] Caccamo A, Oddo S, Sugarman MC, Akbari Y, LaFerla FM (2005) Age- and region-dependent alterations in Abeta-degrading enzymes: implications for Abeta-induced disorders. Neurobiol Aging 26:645–654 source
- Not checked yetcites [50] Fukami S, Watanabe K, Iwata N et al (2002) Abeta-degrading endopeptidase, neprilysin, in mouse brain: synaptic and axonal localization inversely correlating with Abeta pathology. Neurosci Res 43:39–56 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
The paper relies on this without support.
Aging is the most important risk factor for Aβ accumulation and AD.
“since aging is the most important risk factor for Aβ accumulation and AD.”
The paper relies on this without support.
Pathological diagnosis of AD requires Aβ plaques.
“since pathological diagnosis of AD requires Aβ plaques.”
The paper relies on this without support.
APP is normally present at relatively high levels in cells.
“APP, in contrast to Aβ, is normally present at relatively high levels in cells.”
The paper relies on this without support.
Findings in AD transgenic mouse models and cultured neurons reflect mechanisms operating in human AD.
“Comparing AD transgenic to wild-type neurons allowed for biological studies to begin elucidating early intraneuronal Aβ-related abnormalities in neurons.”
The paper relies on this without support.
Immuno-EM detection of Aβ42 in neurites identifies the pathological intraneuronal pool relevant to AD.
“Immuno-EM images of completely abnormal Aβ42 accumulating dystrophic neurites [187, 188], lacking the normal microtubule tracks required for organelle trafficking, secretion and exocytosis, argue against the active secretion of aggregating Aβ42 from neuritis prior to the dissolution of the plasma membrane [95].”
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
“Several studies have shown that both extracellular free Aβ and Aβ-contained EVs play a role in the progression of AD pathology [136–140].”
From Extracellular vesicles as nanotheranostic platforms for targeted neurological disorder interventions (2024) · cites this paper as [139]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Although amyloid beta plaques are extracellular, mounting evidence suggests that aggregation also begins within neurons, where uptake and subsequent degradation within lysosomes has been dysregulated leading to intraneuronal accumulation leading to aggregation [14–20].”
From The Sigma-2 Receptor/TMEM97, PGRMC1, and LDL Receptor Complex Are Responsible for the Cellular Uptake of Aβ42 and Its Protein Aggregates (2020) · cites this paper as [20]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“recent evidence indicates that intraneuronal A accumulation may be an important proximal neurotoxic event in AD pathogenesis (for review see Ref. 56,57).”
From APOE4-specific Changes in Aβ Accumulation in a New Transgenic Mouse Model of Alzheimer Disease (2012) · cites this paper as [56]
In the citing paper
“Intraneuronal Aβ accumulation has been found in the brains of patients presenting AD or mild cognitive impairment [3, 21, 41, 47, 78], and studies suggest that this phenomenon represents an early step in AD neuropathology [40].”
From Senescence-related impairment of autophagy induces toxic intraneuronal amyloid-β accumulation in a mouse model of amyloid pathology (2023) · cites this paper as [40]
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PREDISPOSING LOCUS FOR ALZHEIMER'S DISEASE ON CHROMOSOME 21
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Flagged first, then by citations
4 of the 220 references couldn’t be matched to a known paper.
Research works printed but not linked: 2
- Gouras GK, Takahashi RH (2005) Immunohistocytochemical analysis of amyloid precursor protein and its derivates. In: Xia W, Xu H (eds) Amyloid precursor protein: a practical approach. CRC Press, Florida, pp 155–160
- Tabira T, Chui DH, Kuroda S (2002) Significance of intracellular Abeta42 accumulation in Alzheimer’s disease. Front Biosci 7:a44–a49
Cited by
Sorted by citations
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Amyloid β oligomers in Alzheimer’s disease pathogenesis, treatment, and diagnosis
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Metadata
- Authors
- Gouras, G. K., Tampellini, D., Takahashi, R. H., & Capetillo-Zarate, E.
- Affiliations
- Weill Cornell Medicine (US)
- Tokyo Medical University Hospital (JP)
- Corresponding author
- Gouras, Gunnar K.
- Venue
- Acta Neuropathologica
- Published
- 2010-03-31
- Volume
- 119
- Issue
- 5
- Pages
- 523-541
- ISSN
- 0001-6322 (ISSN-L)
- 1432-0533
- PMC
- PMC3183823
- OpenAlex
- W2063699848
- Semantic Scholar
- 6827a75ab1a7ecbd342dd9dd9bdf866b4dbbddc9
- Cited by
- 372
- References
- 220
- Citations by year
- 2026: 11 · 2025: 21 · 2024: 16 · 2023: 17 · 2022: 23 · 2021: 23 · 2020: 21 · 2019: 20 · 2018: 28 · 2017: 29 · 2016: 25 · 2015: 18 · 2014: 24 · 2013: 27 · 2012: 34
- FWCI
- 3.08
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Acta Neuropathologica (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (R01AG027140, K02AG028174, AG028174, AG027140)
- 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
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, amyloid plaques, amyloid-beta oligomers, amyloid-beta fibrils, amyloid fibril formation, synaptic dysfunction, Alzheimer's disease treatment
- MeSH terms
- Alzheimer Disease, Brain, Humans, Neurons, Synapses, Amyloid beta-Peptides, tau Proteins
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-10-10, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-10 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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