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Cited by 372Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease

Open access
Gouras, Gunnar K., Tampellini, Davide, Takahashi, Reisuke H., Capetillo-Zarate, Estibaliz·2010·Acta Neuropathologica
DOI 10.1007/s00401-010-0679-9PMC PMC3183823
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Abstract

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.

AI snapshot

Written from the paper’s full text.

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.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1007/s00401-010-0679-9

Cites

216 of 216 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 182 cited sources checked · 0 supported · 0 flagged

  • Findingcitation

    FAD mutations cause a relatively greater increase in intracellular compared to secreted Aβ.

    “FAD mutations actually cause a relatively greater increase in intracellular compared to secreted Aβ ([202], and unpublished observations).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • Findingown data

    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.

    “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).”
    Quote in the paperSubstantial claim
  • Findingcitation

    Dementia pugilistica shows considerable intraneuronal Aβ42.

    “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).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [31] Corsellis JA, Bruton CJ, Freeman-Browne D (1973) The aftermath of boxing. Psychol Med 3:270–303 source

      Not checked in the free run.

    • cites [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

      Not checked in the free run.

  • Findingown data

    We observed marked up-regulation of intraneuronal Aβ42 in surrounding neurites and neuron cell bodies near needle track injuries in rodent brains 48 to 72 hours following brain injury.

    “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).”
    Quote in the paperSubstantial claim
  • Findingown data

    By immuno-EM these increases in Aβ42 occurred predominantly in endosomes.

    “By immuno-EM these increases in Aβ42 occurred predominantly in endosomes (Fig. 4b).”
    Quote in the paperSubstantial claim
  • May combine two claims. 40
  • Classified as probably not a substantial claim. 9

  • May combine two claims.

    Premisecitation

    Progressive N-truncation increases the propensity of aggregation and toxicity of Aβ.

    “progressive N-truncation increases the propensity of aggregation [146, 165] and toxicity [23]”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Experimental therapies such as Aβ immunotherapy reduce cerebral Aβ and improve behavior in transgenic mouse models of AD-like cerebral β-amyloidosis.

    “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.”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [178] Solomon B (2007) Clinical immunologic approaches for the treatment of Alzheimer’s disease. Expert Opin Investig Drugs 16:819–828 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In 1993 the first biological paper appeared on the presence of Aβ within cells.

    “In 1993 the first biological paper appeared on the presence of Aβ within cells [201].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Current data suggest a hierarchy in the development of AD that begins with declining levels of Aβ42 in cerebrospinal fluid and accumulation of intraneuronal Aβ42.

    “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”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisenone given

    Pan-Aβ antibodies directed at the Aβ domain detect not only Aβ peptides but also full-length APP and other Aβ-containing APP fragments such as β-secretase cleaved APP βCTFs.

    “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”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationreasoning

    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.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The publication [60] 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.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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 in the free run.

  • May combine two claims.

    Interpretationcitation

    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.

    “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].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [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 in the free run.

    • cites [103] Lin MT, Beal MF (2006) Alzheimer’s APP mangles mitochondria. Nat Med 12:1241–1243 source

      Not checked in the free run.

    • cites [149] Reddy PH (2008) Mitochondrial medicine for aging and neurodegenerative diseases. Neuromolecular Med 10:291–315 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    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.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    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.

    “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.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    A recent study indicated that cognitive decline in AD tracked best with the membranous pool of Aβ42 in brain tissue from human AD; it was concluded that this membrane-associated Aβ42 was cell associated and reflected intraneuronal Aβ42.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    C-terminal specific Aβ42 antibodies typically are best at detecting Aβ42 monomers, and have minimal reactivity against oligomers larger than trimers.

    “C-terminal specific Aβ42 antibodies typically are best at detecting Aβ42 monomers, and have minimal reactivity against oligomers larger than trimers [187].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The presence of intraneuronal Aβ accumulation has now been widely detected in brains of human Down syndrome and AD, and transgenic models of AD, but skepticism persists.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    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.

    “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].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [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 in the free run.

    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Postmortem interval, pre-treatments, counter-stains, fixation and post-fixation, detergent, and blocking solutions can influence interpretation of immuno-histochemistry, and also that of intraneuronal Aβ.

    “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].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    Commercial antibodies can change; particularly polyclonal antibodies can have batch to batch variations that can significantly affect interpretation.

    “it is not common knowledge that commercial antibodies can change. Particularly polyclonal antibodies can have batch to batch variations that can significantly affect interpretation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In a study using ELISA, 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.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    There is variability in the degree of intraneuronal Aβ labeling, which is more pronounced in human compared to AD transgenic mouse brains.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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 in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    One possible explanation for the apparent decrease in intraneuronal Aβ42 with advancing plaque pathology is that Aβ aggregation leads to conformational changes and thereby reduced ability of Aβ antibodies in detecting their antigens.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The triple transgenic mouse expressing mutant APP, PS1 and tau develops early Aβ accumulation in CA1 hippocampal neurons and later tau paired helical filaments.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Early Aβ42 accumulates in layer II entorhinal cortex neuron cell bodies and early plaques occur at their axonal terminal fields in the outer molecular layer of the dentate.

    “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].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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 in the free run.

  • May combine two claims.

    Premisecitation

    A recent E693Delta mutation in APP is associated with an AD clinical phenotype in the absence of plaques; cells harboring this mutation have reduced Aβ secretion and increased intracellular Aβ accumulation and oligomerization.

    “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].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    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).

    “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]).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    The lack of correlation between Aβ plaques and cognitive decline in AD may relate to person-to-person differences in inflammatory cells' ability to remove Aβ plaques.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Neuron cell bodies with early intraneuronal Aβ42 accumulation are those that go on to develop NFTs, while their terminal fields are sites of early plaque pathology.

    “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.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The SLM shows prominent early Aβ42 increases and earliest labeling with phospho-tau antibodies such as AT8.

    “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.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

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  • May combine two claims.

    Premisecitation

    The most marked accumulation of intraneuronal Aβ42 occurs in distal neurites and synaptic compartments as determined by immuno-EM, which cannot be visualized effectively by light or standard immuno-fluorescence microscopy.

    “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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PS1 conditional knockout mice show aberrant accumulation of APP βCTFs in distal axons/pre-synaptic compartments and some in distal dendrites/post-synaptic compartments.

    “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).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    These data provide an early temporal and spatial relationship of the main constituents of the two AD neuropathological hallmarks and link them with synapse pathology.

    “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.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Synapses are major sites of Aβ pathology and generation.

    “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.”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [6] Arendt T (2009) Synaptic degeneration in Alzheimer’s disease. Acta Neuropathol 118:167–179 source

      Not checked in the free run.

    • cites [28] Coleman PD, Yao PJ (2003) Synaptic slaughter in Alzheimer’s disease. Neurobiol Aging 24:1023–1027 source

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    • cites [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 in the free run.

    • cites [119] Mesulam MM (1999) Neuroplasticity failure in Alzheimer’s disease: bridging the gap between plaques and tangles. Neuron 24:521–529 source

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    • cites [168] Selkoe DJ (2002) Alzheimer’s disease is a synaptic failure. Science 298:789–791 source

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  • May combine two claims.

    Interpretationreasoning

    Aging and genetic/environmental risk factors such as apoEε4 and head injury lead to up-regulation and oligomerization of intraneuronal Aβ42 in distal neurites and synapses, which then leads directly to destruction of neurites and synapses from within.

    “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).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    Dense core plaques appear to be derived from neuron cell bodies.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Exogenous application of Aβ alters synaptic plasticity and important synaptic proteins.

    “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.”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [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

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    • cites [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

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    • cites [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

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    • cites [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

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    • cites [177] Snyder EM, Nong Y, Almeida CG et al (2005) Regulation of NMDA receptor trafficking by amyloid-beta. Nat Neurosci 8:1051–1058 source

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  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Patients in coma have marked reductions in extracellular Aβ42, which rises and falls with cognitive improvement and decline.

    “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].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationreasoning

    Degree of intraneuronal Aβ42 might tightly correlate with synaptic dysfunction, whereas synapse-independent factors might dissociate plaque burden from cognitive decline.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Pathological accumulation is most prominent in distal neurites and synapses of AD transgenic mice and provided the first direct association between Aβ and synapse pathologies in the brain.

    “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].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Aβ antibodies can reduce the intraneuronal pool of Aβ in vivo and in vitro; in vitro required Aβ antibody internalization.

    “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.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Sites of high cerebral activity in the default system are sites of early AD neuropathology, but not necessarily because of increased Aβ secretion.

    “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.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Aβ secretion is increased with cognitive activity; in coma patients Aβ rises with cognitive improvement and declines with cognitive decline.

    “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].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Functional brain imaging shows reduced resting brain activity in AD subjects and in genetically at-risk subjects decades before predicted symptoms.

    “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].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Extracellular Aβ1-42 leads to marked up-regulation of endogenously generated Aβ42, which also occurs in neurons.

    “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].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [51] Glabe C (2001) Intracellular mechanisms of amyloid accumulation and pathogenesis in Alzheimer’s disease. J Mol Neurosci 17:137–145 source

      Not checked in the free run.

    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Amyloidogenic processing of APP, and potentially intraneuronal Aβ, is important in extracellular Aβ-induced synapse dysfunction.

    “Recently, additional evidence pointed to the importance of amyloidogenic processing of APP, and therefore potentially intraneuronal Aβ, in extracellular Aβ-induced synapse dysfunction [190].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Neprilysin is the protease shown to most efficiently degrade Aβ and is critical in synaptic activity-induced intraneuronal Aβ42 reduction.

    “The protease shown to most efficiently degrade Aβ, neprilysin [81], was reported to be critical in synaptic activity-induced intraneuronal Aβ42 reduction [190].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    Aβ accumulation begins intracellularly and ends up extracellular following neuritic degeneration.

    “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.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Neprilysin localizes to synapses and declines with aging.

    “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.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [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 in the free run.

    • cites [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

      Not checked in the free run.

45 of 45

  • 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].”
5 of 5

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?

  • Several studies have shown that both extracellular free Aβ and Aβ-contained EVs play a role in the progression of AD pathology.

    “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]

    The Biology section (page not supplied) reports that extracellular Aβ alters synaptic plasticity and proteins, supporting a role for extracellular Aβ in AD pathology. The passages found do not address Aβ-containing extracellular vesicles; their discussion of intracellular endosomes and multivesicular bodies does not establish that EVs contribute to disease progression. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Intraneuronal Aβ accumulation may be an important proximal neurotoxic event in AD pathogenesis.

    “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]

  • Intraneuronal Aβ accumulation has been found in the brains of patients presenting AD or mild cognitive impairment and is suggested to represent an early step in AD neuropathology.

    “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]

Cites

1 retracted

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

  1. 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
  2. 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

Related

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.
ORCID
Venue
Acta Neuropathologica
Publisher
Springer Science and Business Media LLC
Published
2010-03-31
Volume
119
Issue
5
Pages
523-541
ISSN
  • 0001-6322 (ISSN-L)
  • 1432-0533
DOI
10.1007/s00401-010-0679-9
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
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
  • Health Sciences › Medicine › Physiology › 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.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

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.

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