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Alzheimer’s-Causing Mutations Shift Aβ Length by Destabilizing γ-Secretase-Aβn Interactions
Open accessAbstract
Alzheimer's disease (AD)-linked mutations in Presenilins (PSEN) and the amyloid precursor protein (APP) lead to production of longer amyloidogenic Aβ peptides. The shift in Aβ length is fundamental to the disease; however, the underlying mechanism remains elusive. Here, we show that substrate shortening progressively destabilizes the consecutive enzyme-substrate (E-S) complexes that characterize the sequential γ-secretase processing of APP. Remarkably, pathogenic PSEN or APP mutations further destabilize labile E-S complexes and thereby promote generation of longer Aβ peptides. Similarly, destabilization of wild-type E-S complexes by temperature, compounds, or detergent promotes release of amyloidogenic Aβ. In contrast, E-Aβ n stabilizers increase γ-secretase processivity. Our work presents a unifying model for how PSEN or APP mutations enhance amyloidogenic Aβ production, suggests that environmental factors may increase AD risk, and provides the theoretical basis for the development of γ-secretase/substrate stabilizing compounds for the prevention of AD.
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“Thus, GDE2 loss leads to an increase in Aβ peptides, in particular, the longer Aβ42 peptide associated with pathogenic Aβ species (31).”
From GDE2-RECK controls ADAM10 α-secretase–mediated cleavage of amyloid precursor protein (2021) · cites this paper as [31]
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“Building on the chemoinformatic findings that stability and hydrophobic packing60 control substrate processing kinetics proposed by Okochi et al.,89 these various findings were formalized in the FIST (fit-stay-trim) model (Figure 3), where the TMs (2, 3, 6, 7, 9) are the “fingers” of the fist that “squeeze” the substr…”
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“Less frequent forms of AD, called familial or earlyonset AD, are mainly caused by autosomal dominant inherited mutations in amyloid precursor protein (APP) and presenilin (PSEN) genes, triggering the formation of amyloid plaques (Chévez-Gutiérrez et al., 2012; Szaruga et al., 2017).”
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Self-citationAmyloid β, γ-secretase, and familial Alzheimer's disease
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Self-citationThe pathogenicity of PSEN2 variants is tied to Aβ production and homology to PSEN1
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CTAD taskforce: genetic therapies in Alzheimer’s disease
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“There are strong correlations between the ratios of longer ( ≥ 42) to shorter ( 42) A ß lengths and predicted age of onset of ADAD [13,14].”
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Substrate–Enzyme Interactions in Intramembrane Proteolysis: γ-Secretase as the Prototype
Liu, X., Zhao, J., Zhang, Y., Ubarretxena‐Belandia, I., Forth, S. T., Lieberman, R. L., & Wang, C. (2020) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2020.00065 · Cited by 6
Amyloidogenic and anti-amyloidogenic properties of presenilin 1
Bustos, V., Pulina, M. V., & Ledo, J. H. (2020) · Advances in pharmacology · doi:10.1016/bs.apha.2020.09.010 · Cited by 6
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“Mutations in PSEN1 destabilise the enzyme-sub-strate complex, thereby releasing longer forms of Aβ prior to complete processing [15–17].”
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Sleep is bi-directionally modified by amyloid beta oligomersPreprint
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“…the natural daily fluctuation in body temperature (in humans, up to 2°C) or the induction of a fever can promote changes in amyloidogenic Aβ generation (Szaruga et al., 2017) In addition, Aβ can act as an antimicrobial peptide (Kumar et al., 2016; Soscia et al., 2010), and microbial infection can…”
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A Pathogenic Presenilin-1 Val96Phe Mutation from a Malaysian Family
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“The recognition that Aβ peptides, despite lower affinities, can compete with APP-CTFs for binding to γ-secretase, when present at relatively high concentrations (30), led us to propose a mechanism that connects increases in the Aβ42 peptide with”
BackgroundMethodInfluentialSelf-citationFamilial cerebral amyloid disorders with prominent white matter involvement
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Self-citationGlutamate Transporter 1 as a Novel Negative Regulator of Amyloid β
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“As the catalytic component of the γ -secretase complex is encoded by PSEN1 and PSEN2 , mutations in those genes disrupt APP processing, leading to increased A β accumulation [53].”
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“Mutations in PSEN1 or PSEN2 may cause the structural instability of γ-secretase, which affects the production of longer Aβ peptides during APP processing [8].”
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γ-Secretase modulation and plaque regression in Alzheimer’s disease
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Quantifying correlations between mutational sites in the catalytic subunit of γ-secretase
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Background
Metadata
- Authors
- Szaruga, M., Munteanu, B., Lismont, S., Veugelen, S., Horré, K., Mercken, M., Saido, T. C., Ryan, N. S., De Vos, T., Savvides, S. N., Gallardo, R., Schymkowitz, J., Rousseau, F., Fox, N. C., Hopf, C., De Strooper, B., & Chávez-Gutiérrez, L.
- Affiliations
- Technische Hochschule Mannheim (DE)
- VIB-KU Leuven Center for Brain & Disease Research (BE)
- Janssen (Belgium) (BE)
- RIKEN Center for Brain Science (JP)
- University College London (GB)
- Ghent University (BE)
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2017-07
- Volume
- 170
- Issue
- 3
- Pages
- 443-456.e14
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W2742157915
- Cited by
- 248
- References
- 59
- Citations by year
- 2026: 12 · 2025: 15 · 2024: 35 · 2023: 29 · 2022: 27 · 2021: 30 · 2020: 44 · 2019: 32 · 2018: 20 · 2017: 4
- FWCI
- 20.51
- Type
- journal article
- Language
- en
- Update notices
- erratum (2021-04-15)
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Lirias (submittedVersion)
- Funders
- European Regional Development Fund
- Agentschap voor Innovatie door Wetenschap en Technologie
- KU Leuven (OT/12/092, METH/14/07)
- European Research Council
- Janssen Pharmaceuticals
- Ministerium für Wissenschaft, Forschung und Kunst Baden-Württemberg
- Herculesstichting (AUGE/11/029)
- Fonds Wetenschappelijk Onderzoek (G074115)
- Deutsche Forschungsgemeinschaft (1S16516N, INST 874/7-1 FUGG, SB/131289)
- Belgian Federal Science Policy Office (P7/16)
- 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
- Alzheimer's disease, gamma-secretase, presenilin mutations, amyloid precursor protein mutations, temperature dependence of enzyme activity, detergent effects on enzyme activity, Alzheimer's disease prevention
- MeSH terms
- Alzheimer Disease, Animals, Brain, Cell Line, Enzyme Stability, Female, Humans, Membrane Proteins, Models, Molecular, Mutation, Peptide Hydrolases, Endopeptidases, Amyloid beta-Protein Precursor, Mice, Presenilin-1, HEK293 Cells
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