Cited by 485Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

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The presenilin hypothesis of Alzheimer’s disease: Evidence for a loss-of-function pathogenic mechanism.

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Shen, Jie, Kelleher, Raymond J.·2007·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.0608332104PMC PMC1766397

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Abstract

Dominantly inherited mutations in the genes encoding presenilins (PS) and the amyloid precursor protein (APP) are the major causes of familial Alzheimer's disease (AD). The prevailing view of AD pathogenesis posits that accumulation of β-amyloid (Aβ) peptides, particularly Aβ42, is the central event triggering neurodegeneration. Emerging evidence, however, suggests that loss of essential functions of PS could better explain dementia and neurodegeneration in AD. First, conditional inactivation of PS in the adult mouse brain causes progressive memory loss and neurodegeneration resembling AD, whereas mouse models based on overproduction of Aβ have failed to produce neurodegeneration. Second, whereas pathogenic PS mutations enhance Aβ42 production, they typically reduce Aβ40 generation and impair other PS-dependent activities. Third, γ-secretase inhibitors can enhance the production of Aβ42 while blocking other γ-secretase activities, thus mimicking the effects of PS mutations. Finally, PS mutations have been identified in frontotemporal dementia, which lacks amyloid pathology. Based on these and other observations, we propose that partial loss of PS function may underlie memory impairment and neurodegeneration in the pathogenesis of AD. We also speculate that Aβ42 may act primarily to antagonize PS-dependent functions, possibly by operating as an active site-directed inhibitor of γ-secretase.

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Authors: Shen, J., & Kelleher, R. J.
Affiliations: Brigham and Women's Hospital (US)
Harvard University (US)
ORCID: Shen, Jie
Venue: Proceedings of the National Academy of Sciences
Publisher: National Academy of Sciences
Published: 2007-01-09
Volume: 104
Issue: 2
Pages: 403-409
ISSN: 0027-8424 (ISSN-L)
1091-6490
DOI: 10.1073/pnas.0608332104
PMC: PMC1766397
OpenAlex: W2041601288
Cited by: 485
References: 62
Citations by year: 2026: 9 · 2025: 14 · 2024: 22 · 2023: 32 · 2022: 16 · 2021: 20 · 2020: 31 · 2019: 21 · 2018: 19 · 2017: 26 · 2016: 24 · 2015: 20 · 2014: 14 · 2013: 31 · 2012: 32
FWCI: 3.36
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Proceedings of the National Academy of Sciences (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: Alzheimer's Association
National Institutes of Health
National Institute of Neurological Disorders and Stroke (RF1NS041783, R01NS041783)
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: presenilin, Alzheimer's disease, familial Alzheimer's disease, loss-of-function mechanism, amyloid precursor protein, amyloid-beta, amyloid-beta 42, Aβ40, gamma-secretase, gamma-secretase inhibitors, conditional knockout mice, memory loss, neurodegeneration, frontotemporal dementia, presenilin mutations
MeSH terms: Alzheimer Disease, Amino Acid Sequence, Animals, Brain, Disease Models, Animal, Humans, Models, Neurological, Molecular Sequence Data, Mutation, Nerve Degeneration, Amyloid beta-Protein Precursor, Mice, Knockout, Mice, Presenilins, Amyloid Precursor Protein Secretases

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The presenilin hypothesis of Alzheimer’s disease: Evidence for a loss-of-function pathogenic mechanism.

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