Cited by 70Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

APP accumulates with presynaptic proteins around amyloid plaques: A role for presynaptic mechanisms in Alzheimer's disease?

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Jordà‐Siquier, Tomàs, Petrel, Melina, Kouskoff, Vladimir, Smailovic, Una, Cordelières, Fabrice, Frykman, Susanne, Müller, Ulrike, Mulle, Christophe +1 more·2022·Alzheimer's & Dementia

Abstract

In Alzheimer's disease (AD), the distribution of the amyloid precursor protein (APP) and its fragments other than amyloid beta, has not been fully characterized. Here, we investigate the distribution of APP and its fragments in human AD brain samples and in mouse models of AD in reference to its proteases, synaptic proteins, and histopathological features characteristic of the AD brain, by combining an extensive set of histological and analytical tools. We report that the prominent somatic distribution of APP observed in control patients remarkably vanishes in human AD patients to the benefit of dense accumulations of extra‐somatic APP, which surround dense‐core amyloid plaques enriched in APP‐Nter. These features are accentuated in patients with familial forms of the disease. Importantly, APP accumulations are enriched in phosphorylated tau and presynaptic proteins whereas they are depleted of post‐synaptic proteins suggesting that the extra‐somatic accumulations of APP are of presynaptic origin. Ultrastructural analyses unveil that APP concentrates in autophagosomes and in multivesicular bodies together with presynaptic vesicle proteins. Altogether, alteration of APP distribution and its accumulation together with presynaptic proteins around dense‐core amyloid plaques is a key histopathological feature in AD, lending support to the notion that presynaptic failure is a strong physiopathological component of AD.

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Crossref · 10.1002/alz.12546

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  • APP is a marker of axonal degeneration and accumulates in presynaptic terminals, indicative of dystrophic neurons surrounding amyloid plaques.

    “Previous studies have established APP as a marker of axonal degeneration54,55 and demonstrated its accumulation in presynaptic terminals, indicative of dystrophic neurons surrounding amyloid plaques.56”

    From Amyloid-β induces lipid droplet-mediated microglial dysfunction via the enzyme DGAT2 in Alzheimer’s disease (2025) · cites this paper as [56]

    The Results report APP accumulations around amyloid plaques enriched in presynaptic proteins, and the study conclusions describe presynaptic APP within dystrophic axons (page numbers unavailable). However, the paper places the accumulations at axon terminals only presumptively; it does not demonstrate that they are in presynaptic terminals. The axonal-degeneration marker claim is attached to citations 54 and 55, not this citation. (LLM, conf=0.85)

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Research works printed but not linked: 1

  1. [57]Barthet G, Mulle C. Presynaptic failure in Alzheimer's disease. Prog Neurobiol. 2020; 194: 101801. 32428558

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Authors
Jordà‐Siquier, T., Petrel, M., Kouskoff, V., Smailovic, U., Cordelières, F., Frykman, S., Müller, U., Mulle, C., & Barthet, G.
Affiliations
  • University Bordeaux, CNRS, Interdisciplinary Institute for Neuroscience, IINS, UMR 5297 Bordeaux France
  • University Bordeaux, CNRS, INSERM, Bordeaux Imaging Center, BIC, UMS 3420, US 4 Bordeaux France
  • Centre National de la Recherche Scientifique (FR)
  • Division of Neurogeriatrics, Center for Alzheimer Research, Department of Neurobiology, Care Sciences and Society Karolinska Institutet Solna Sweden
  • Karolinska Institutet (SE)
  • Heidelberg University (DE)
Corresponding author
Barthet, Gaël
Venue
Alzheimer's & Dementia
Publisher
Wiley
Published
2022-01-25
Volume
18
Issue
11
Pages
2099-2116
ISSN
  • 1552-5260 (ISSN-L)
  • 1552-5279
OpenAlex
W4210588922
Cited by
63
References
85
Citations by year
2026: 10 · 2025: 13 · 2024: 22 · 2023: 9 · 2022: 9
FWCI
9.44
Type
journal article
Language
en
Open access
Locations
  • Alzheimer s & Dementia (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • HAL (submittedVersion)
Funders
Fondation pour la Recherche Médicale (#DEQ20160334900)
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
amyloid precursor protein, Alzheimer's disease
MeSH terms
Alzheimer Disease, Animals, Brain, Humans, Mice, Transgenic, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Mice, Plaque, Amyloid

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