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The presenilin hypothesis of Alzheimer’s disease: Evidence for a loss-of-function pathogenic mechanism.
Open accessAbstract
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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“This broad and mixed response is consistent with the wider perturbation of interleukin, TGF-β, Wnt, glutamatergic, and presenilin signaling observed in our pathway analysis and with previous evidence that presenilins influence synaptic function and intracellular calcium homeostasis (Ho and Shen, 2011; Shen and Kelleher, 2007).”
From Isogenic human stem cell models reveal mutation-dependent protective mechanisms of APOE3 Christchurch (2026) · cites this paper as Shen and Kelleher, 2007
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Metadata
- 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
- 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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