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Cited by 74Alzheimer's disease research and treatmentsNeuroscience and Neuropharmacology ResearchDementia and Cognitive Impairment Research

Presynaptic failure in Alzheimer's disease

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Barthet, Gael, Mulle, Christophe·2020·Progress in Neurobiology
DOI 10.1016/j.pneurobio.2020.101801
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Abstract

Synaptic loss is the best correlate of cognitive deficits in Alzheimer's disease (AD). Extensive experimental evidence also indicates alterations of synaptic properties at the early stages of disease progression, before synapse loss and neuronal degeneration. A majority of studies in mouse models of AD have focused on post-synaptic mechanisms, including impairment of long-term plasticity, spine structure and glutamate receptor-mediated transmission. Here we review the literature indicating that the synaptic pathology in AD includes a strong presynaptic component. We describe the evidence indicating presynaptic physiological functions of the major molecular players in AD. These include the amyloid precursor protein (APP) and the two presenilin (PS) paralogs PS1 or PS2, genetically linked to the early-onset form of AD, in addition to tau which accumulates in a pathological form in the AD brain. Three main mechanisms participating in presynaptic functions are highlighted. APP fragments bind to presynaptic receptors (e.g. nAChRs and GABA B receptors), presenilins control Ca 2+ homeostasis and Ca 2+-sensors, and tau regulates the localization of presynaptic molecules and synaptic vesicles. We then discuss how impairment of these presynaptic physiological functions can explain or forecast the hallmarks of synaptic impairment and associated dysfunction of neuronal circuits in AD. Beyond the physiological roles of the AD-related proteins, studies in AD brains also support preferential presynaptic alteration. This review features presynaptic failure as a strong component of pathological mechanisms in AD.

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Authors
Barthet, G., & Mulle, C.
Affiliations
Centre National de la Recherche Scientifique (FR)
Corresponding author
Mulle, Christophe
ORCID
Mulle, Christophe
Venue
Progress in Neurobiology
Publisher
Elsevier BV
Published
2020-11
Volume
194
Pages
101801
ISSN
0301-0082 (ISSN-L)
DOI
10.1016/j.pneurobio.2020.101801
OpenAlex
W3024317714
Cited by
74
References
173
Citations by year
2026: 7 · 2025: 11 · 2024: 13 · 2023: 14 · 2022: 8 · 2021: 15 · 2020: 5 · 2019: 1
FWCI
1.34
Type
journal article
Language
en
Open access
Licence
Locations
  • Progress in Neurobiology (acceptedVersion)
  • PubMed (publishedVersion)
  • HAL (submittedVersion, cc-by-nc)
Funders
  • Association France Alzheimer
  • Fondation Plan Alzheimer
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
Alzheimer's disease, presynaptic dysfunction, synaptic loss, amyloid precursor protein, presenilin, tau protein, nicotinic acetylcholine receptors, GABAB receptors, calcium homeostasis, synaptic vesicles, neural circuits, mouse models of Alzheimer's disease
MeSH terms
Alzheimer Disease, Animals, Humans, Synaptic Transmission, Amyloid beta-Protein Precursor, tau Proteins, Receptors, Presynaptic, Presynaptic Terminals, Presenilins

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