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Cited by 255Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Presenilin-1 mutations and Alzheimer’s disease.

Open access
Kelleher, Raymond J., Shen, Jie·2017·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.1619574114PMC PMC5278466
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Abstract

Mutations in the PSEN1 gene, encoding presenilin-1 (PS1), are the most common cause of familial Alzheimer’s disease (FAD). PS1 functions as the catalytic subunit of γ-secretase, an intramembranous protease that cleaves a variety of type 1 transmembrane proteins, notably including the amyloid precursor protein (APP) and Notch. Following prior cleavage by β-secretase, processing of APP by γ-secretase generates β-amyloid (Aβ) peptides of varying lengths. Whereas Aβ40 accounts for ∼90% of Aβ production, the minor Aβ42 product is more hydrophobic and is thought to nucleate Aβ aggregation, leading to amyloid plaque deposition in the AD brain. In PNAS, Sun et al. (1) used an in vitro system to evaluate the effects of 138 pathogenic mutations in PSEN1 on the production of Aβ40 and Aβ42, and their findings provide valuable perspectives on pathogenic mechanisms in AD. The authors’ systematic analysis of mutations affecting all PS1 residues altered in FAD provides an unprecedented perspective on the impact of PSEN1 mutations on Aβ production and γ-secretase activity. The mechanism by which PSEN1 mutations lead to neurodegeneration and dementia in FAD remains hotly debated. Two distinct but not mutually exclusive hypotheses have been proposed to explain how PSEN1 mutations cause FAD (2, 3). The amyloid hypothesis proposed that PSEN1 mutations initiate disease pathogenesis by increasing production of Aβ42 (2). This view was based on initial studies in which small numbers of clinical PSEN1 mutations were found to increase levels of Aβ42 in plasma of FAD patients, transfected cells, and transgenic mice, leading to the notion that PSEN1 mutations triggered FAD pathogenesis by enhancing APP processing and inducing excessive production of Aβ42 (2, 4⇓–6). As inconsistencies with this model subsequently emerged, revision of the amyloid hypothesis shifted the focus to relative rather than absolute increases in Aβ42 production, and the ability … [↵][1]1To whom correspondence should be addressed. Email: jshen{at}rics.bwh.harvard.edu. [1]: #xref-corresp-1-1

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  • The absence of the effect on net extracellular Aβ in PS1E280A cultures suggests that when γ-secretase activity is directly altered by PSEN1 mutations, upstream modulation by APOE3ch is insufficient to reduce net extracellular Aβ levels.

    “The absence of this effect in PS1E280A cultures suggests that when γ-secretase activity is directly altered by PSEN1 mutations (Kelleher and Shen, 2017), upstream modulation by APOE3ch is insufficient to reduce net extracellular Aβ levels.”

    From Isogenic human stem cell models reveal mutation-dependent protective mechanisms of APOE3 Christchurch (2026) · cites this paper as Kelleher and Shen, 2017

  • Mutations in APP and PSEN account for only a small proportion of early-onset familial AD cases.

    “Although mutations in amyloid precursor protein (APP) and presenilins (PSEN1, PSEN2) account for only a small proportion of early‐onset familial AD cases, 4 , 5”

    From Aberrant phase separation from a rare <i>ABI3</i> mutation drives microglial dysfunction and Alzheimer's risk (2026) · cites this paper as [5]

    The opening passage (page not available) calls PSEN1 mutations the most common cause of familial Alzheimer’s disease, and a later passage discusses onset ages for people with PSEN or APP mutations. Neither gives the proportion of early-onset familial cases attributable to APP and presenilin mutations. Searches for that proportion found no passage addressing it; 'most common cause' does not establish or refute that the combined proportion is small. (LLM, conf=0.73)

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Research works printed but not linked: 13

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Cited by

Sorted by citations

Authors
Kelleher, R. J., & Shen, J.
Affiliations
  • Harvard University (US)
  • Brigham and Women's Hospital (US)
ORCID
Shen, Jie
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2017-01-12
Volume
114
Issue
4
Pages
629-631
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.1619574114
PMC
PMC5278466
OpenAlex
W2571803537
Cited by
255
References
8
Citations by year
2026: 26 · 2025: 23 · 2024: 36 · 2023: 29 · 2022: 27 · 2021: 41 · 2020: 33 · 2019: 20 · 2018: 16 · 2017: 4
FWCI
14.20
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health
  • National Institute of Neurological Disorders and Stroke (R01NS075346, RF1NS041783, R01NS042818, K24NS093185, R01NS041783)
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
presenilin 1, Alzheimer's disease, presenilin 1 mutations, genetic susceptibility, amyloid-beta processing, gamma-secretase
MeSH terms
Alzheimer Disease, Humans, Mutation, Amyloid beta-Protein Precursor, Presenilin-1, Presenilin-2

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