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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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“This balance, however, seems to be rather delicate and can be shifted toward the production of longer amino acid chains (predominantly Aβ42) by several factors, such as mutations and changes of bilayer composition or temperature (Holmes et al., 2012; Szaruga et al., 2017).”
BackgroundBiomarkers associated with the pathogenesis of Alzheimer’s disease
Wang, H., Sun, M., Li, W., Liu, X., Zhu, M., & Qin, H. (2023) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2023.1279046 · Cited by 35
“Szaruga et al. (2017) used a progressive temperature increase method to demonstrate that wild-type γ -secretase production of the “disease-like” A β peptide is induced with increasing temperature.”
BackgroundMethodInfluentialEscamilla-Ayala, A. A., Sannerud, R., Mondin, M., Poersch, K., Vermeire, W., Paparelli, L., Berlage, C., Koenig, M., Chavez-Gutierrez, L., Ulbrich, M. H., et al. (2020) · eLife · doi:10.7554/elife.56679 · Cited by 29
Self-citationAberrant splicing of PSEN2 , but not PSEN1 , in individuals with sporadic Alzheimer’s disease
Course, M. M., Gudsnuk, K. M., Keene, C. D., Bird, T. D., Jayadev, S., & Valdmanis, P. N. (2022) · Brain · doi:10.1093/brain/awac294 · Cited by 33
Enzlein, T., Cordes, J., Munteanu, B., Michno, W., Serneels, L., Strooper, B. D., Hanrieder, J., Ivo Wolf, A., Chávez‐Gutiérrez, L., & Hopf, C. (2020) · Analytical Chemistry · doi:10.1021/acs.analchem.0c02585 · Cited by 28
Self-citationPlasma amyloid-β ratios in autosomal dominant Alzheimer’s disease: the influence of genotype
O’Connor, A., Pannee, J., Poole, T., Arber, C., Portelius, E., Swift, I. J., Heslegrave, A., Abel, E., Willumsen, N., Rice, H., et al. (2021) · Brain · doi:10.1093/brain/awab166 · Cited by 30
“PSEN1 mutations are associated with destabilization of the enzyme–substrate complex.(10) It will be important for future research”
BackgroundSelf-citationUrban, A. S., Pavlov, K. V., Kamynina, A. V., Okhrimenko, I. S., Arseniev, A. S., & Bocharov, E. V. (2021) · Molecules · doi:10.3390/molecules26102897 · Cited by 30
“The supporting genetic evidence includes the fact that the familial mutations associated with the early onset of AD are mostly localized in the genes encoding APP or the secretases involved in its proteolysis [3,12,13].”
BackgroundGuix, F. X. (2019) · Journal of Neuroscience Research · doi:10.1002/jnr.24526 · Cited by 30
“FAD mutations on presenilin and APP increase the length of the Aβ peptides generated, which show a higher propensity to aggregate and toxicity (Szaruga et al., 2017).”
BackgroundIntegrative Single-Plaque Analysis Reveals Signature Aβ and Lipid Profiles in the Alzheimer’s Brain
Enzlein, T., Lashley, T., Sammour, D. A., Hopf, C., & Chávez‐Gutiérrez, L. (2024) · Analytical Chemistry · doi:10.1021/acs.analchem.3c05557 · Cited by 28
Self-citationCai, T., Yonaga, M., & Tomita, T. (2017) · Journal of Neuroscience · doi:10.1523/jneurosci.1628-17.2017 · Cited by 28
“Recent enzymatic and genetic analyses demonstrated that increased or decreased A 42 production is associated with a partial loss- or gain-of-function of -secretase, respectively (ChávezGutiérrez et al., 2012; Takeo et al., 2014; Szaruga et al., 2015, 2017; Futai et al., 2016).”
BackgroundYong, Y., Zhang, R., Liu, Z., Wei, D., Shang, Y., Wu, J., Zhang, Z., Li, C., Chen, Z., & Bian, H. (2019) · The Journal of Pathology · doi:10.1002/path.5316 · Cited by 28
Trambauer, J., Fukumori, A., & Steiner, H. (2020) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2020.01.011 · Cited by 28
Amyloid-β1–43 cerebrospinal fluid levels and the interpretation of APP, PSEN1 and PSEN2 mutations
Perrone, F., Bjerke, M., Hens, E., Sieben, A., Timmers, M., Roeck, A. D., Vandenberghe, R. R., Sleegers, K., Martin, J., Deyn, P. P. D., et al. (2020) · Alzheimer s Research & Therapy · doi:10.1186/s13195-020-00676-5 · Cited by 28
“roborate previous findings on Aβ1–43 [21, 25, 26, 29, 49], suggesting a possible involvement of longer Aβ peptides”
BackgroundResultSelf-citationYu, Y., Liu, D.-Y., Chen, X.-S., Zhu, L., & Wan, L. (2021) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2021/6467679 · Cited by 28
“Alzheimer’s disease (AD) is another common neurodegenerative disorder caused by extensive neuroinflammation and massive neuron loss [55].”
BackgroundCallens, M., Loncke, J., & Bultynck, G. (2022) · Cells · doi:10.3390/cells11121963 · Cited by 30
Do, H. N., Devkota, S., Bhattarai, A., Wolfe, M. S., & Miao, Y. (2023) · Communications Biology · doi:10.1038/s42003-023-04539-1 · Cited by 27
Structure and dynamics of γ-secretase with presenilin 2 compared to presenilin 1
Dehury, B., Tang, N., Blundell, T. L., & Kepp, K. P. (2019) · RSC Advances · doi:10.1039/c9ra02623a · Cited by 27
High temperature promotes amyloid β-protein production and γ-secretase complex formation via Hsp90
Noorani, A. A., Yamashita, H., Gao, Y., Islam, S., Sun, Y., Nakamura, T., Enomoto, H., Zou, K., & Michikawa, M. (2020) · Journal of Biological Chemistry · doi:10.1074/jbc.ra120.013845 · Cited by 27
A short perspective on the long road to effective treatments for Alzheimer's disease
Reynolds, D. S. (2019) · British Journal of Pharmacology · doi:10.1111/bph.14581 · Cited by 28
Insights into membrane-bound presenilin 2 from all-atom molecular dynamics simulations
Dehury, B., Tang, N., & Kepp, K. P. (2019) · Journal of Biomolecular Structure and Dynamics · doi:10.1080/07391102.2019.1655481 · Cited by 27
“FAD mutations may impair catalytic activity by changing the conformational interaction with c-secretase substrates (Ch avezGuti errez et al., 2012; Szaruga et al., 2017).”
BackgroundDiscovery of Cellular Roles of Intramembrane Proteases
Beard, H. A., Barniol‐Xicota, M., Yang, J., & Verhelst, S. H. L. (2019) · ACS Chemical Biology · doi:10.1021/acschembio.9b00404 · Cited by 25
The dynamics of γ-secretase and its substrates
Hitzenberger, M., Götz, A., Menig, S., Brunschweiger, B., Zacharias, M., & Scharnagl, C. (2020) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2020.04.008 · Cited by 30
Structural Modeling of γ-Secretase Aβ n Complex Formation and Substrate Processing
Hitzenberger, M., & Zacharias, M. (2019) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.8b00725 · Cited by 26
Dinkel, F., Trujillo-Rodriguez, D., Villegas, A., Streffer, J., Mercken, M., Lopera, F., Glatzel, M., & Sepulveda-Falla, D. (2020) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2020.00220 · Cited by 23
“Further studies should assess if truncated Aβ species play a larger role in CAA in PS1 FAD.”
ResultInfluentialSelf-citationSpatially resolved mass spectrometry analysis of amyloid plaque‐associated lipids
Blank, M., & Hopf, C. (2020) · Journal of Neurochemistry · doi:10.1111/jnc.15216 · Cited by 24
“Their level of aggregation and toxicity depends on the equilibrium between monomeric, oligomeric, and fibrillary forms and, recently, long forms of Aβpeptides have prominently been implicated in AD etiology (Szaruga et al., 2017).”
BackgroundSelf-citationTakasugi, N., Komai, M., Kaneshiro, N., Ikeda, A., Kamikubo, Y., & Uehara, T. (2023) · Cells · doi:10.3390/cells12030454 · Cited by 29
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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