Alzheimer's Disease-Linked Mutations in Presenilin-1 Result in a Drastic Loss of Activity in Purified γ-Secretase Complexes
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BACKGROUND: Mutations linked to early onset, familial forms of Alzheimer's disease (FAD) are found most frequently in PSEN1, the gene encoding presenilin-1 (PS1). Together with nicastrin (NCT), anterior pharynx-defective protein 1 (APH1), and presenilin enhancer 2 (PEN2), the catalytic subunit PS1 constitutes the core of the γ-secretase complex and contributes to the proteolysis of the amyloid precursor protein (APP) into amyloid-beta (Aβ) peptides. Although there is a growing consensus that FAD-linked PS1 mutations affect Aβ production by enhancing the Aβ1-42/Aβ1-40 ratio, it remains unclear whether and how they affect the generation of APP intracellular domain (AICD). Moreover, controversy exists as to how PS1 mutations exert their effects in different experimental systems, by either increasing Aβ1-42 production, decreasing Aβ1-40 production, or both. Because it could be explained by the heterogeneity in the composition of γ-secretase, we purified to homogeneity complexes made of human NCT, APH1aL, PEN2, and the pathogenic PS1 mutants L166P, ΔE9, or P436Q. METHODOLOGY/PRINCIPAL FINDINGS: We took advantage of a mouse embryonic fibroblast cell line lacking PS1 and PS2 to generate different stable cell lines overexpressing human γ-secretase complexes with different FAD-linked PS1 mutations. A multi-step affinity purification procedure was used to isolate semi-purified or highly purified γ-secretase complexes. The functional characterization of these complexes revealed that all PS1 FAD-linked mutations caused a loss of γ-secretase activity phenotype, in terms of Aβ1-40, Aβ1-42 and APP intracellular domain productions in vitro. CONCLUSION/SIGNIFICANCE: Our data support the view that PS1 mutations lead to a strong γ-secretase loss-of-function phenotype and an increased Aβ1-42/Aβ1-40 ratio, two mechanisms that are potentially involved in the pathogenesis of Alzheimer's disease.
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Familial EOAD mutations in PSEN1 and PSEN2 typically result in an increased production of longer and more aggregation-prone derivatives of APP such as Aβ1-42.
“familial EOAD mutations in PSEN1 and PSEN2 typically result in an increased production of longer and more aggregation-prone derivatives of APP such as Aβ1–42 [47–49].”
From Genetic architecture of Alzheimer's disease (2020) · cites this paper as [49]
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“Similar to some mutations in APP, familial EOAD mutations in PSEN1 and PSEN2 typically result in an increased production of longer and more aggregation-prone derivatives of APP such as Aβ1–42 (Citron et al., 1997; Mehta et al., 1998; Cacquevel et al., 2012).”
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- Authors
- Cacquevel, M., Aeschbach, L., Houacine, J., & Fraering, P. C.
- Affiliations
- University of Chieti-Pescara (IT)
- École Polytechnique Fédérale de Lausanne (CH)
- Corresponding author
- Fraering, Patrick C.
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2012-04-18
- Volume
- 7
- Issue
- 4
- Pages
- e35133
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3329438
- OpenAlex
- W2150684193
- Cited by
- 75
- References
- 10
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 1 · 2023: 7 · 2022: 4 · 2021: 9 · 2020: 6 · 2019: 10 · 2018: 6 · 2017: 6 · 2016: 8 · 2015: 3 · 2014: 4 · 2013: 4 · 2012: 1
- FWCI
- 2.57
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion)
- 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
- Alzheimer's disease, presenilin 1, familial Alzheimer's disease, gamma-secretase, PSEN1 mutations, amyloid-beta 42, Aβ40, APP intracellular domain, nicastrin, Pen-2, loss-of-function phenotypes, APP processing
- MeSH terms
- Alzheimer Disease, Animals, Cell Line, Enzyme Activation, Fibroblasts, Humans, Mutation, Phenotype, Gene Expression, Mice, Presenilin-1, Amyloid Precursor Protein Secretases
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