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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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Cites
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Scheltens, P., De Strooper, B., Kivipelto, M., Holstege, H., Chételat, G., Teunissen, C. E., Cummings, J., & van der Flier, W. M. (2021) · The Lancet · doi:10.1016/s0140-6736(20)32205-4 · Cited by 5,465
Microglia in Alzheimer’s disease
Hansen, D. V., Hanson, J. E., & Sheng, M. (2018) · Journal of Cell Biology · doi:10.1083/jcb.201709069 · Cited by 1,935
Nguyen, P. H., Ramamoorthy, A., Sahoo, B. R., Zheng, J., Faller, P., Straub, J. E., Domínguez, L., Shea, J., Dokholyan, N. V., Simone, A. D., et al. (2021) · Chemical Reviews · doi:10.1021/acs.chemrev.0c01122 · Cited by 680
Inflammatory Processes in Alzheimer’s Disease—Pathomechanism, Diagnosis and Treatment: A Review
Twarowski, B., & Herbet, M. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24076518 · Cited by 489
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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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