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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GDE2 loss leads to an increase in Aβ peptides, in particular the longer Aβ42 peptide associated with pathogenic Aβ species.
“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]
The Introduction identifies long Aβ peptides, including Aβ42, as relevant to the formation of toxic species in Alzheimer’s disease. But the paper examines PSEN and APP mutations, not GDE2 loss; it does not support the claim that GDE2 loss increases Aβ peptides or Aβ42 specifically. (LLM, conf=0.87)
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“In this regard, our previous studies have demonstrated that FAD-linked mutations in PSEN1 share a common mechanism: they destabilize GSEC-APP/A β n (Enzyme-Substrate, E-S) interactions during the sequential proteolysis, and thereby promote the premature release of longer A β n peptides [29].”
InfluentialSelf-citationGenetics, Functions, and Clinical Impact of Presenilin-1 (PSEN1) Gene
Bagaria, J., Bagyinszky, E., & An, S. S. A. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms231810970 · Cited by 114 · see citing works
Selective ferroptosis vulnerability due to familial Alzheimer’s disease presenilin mutations
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“While the impact of PS mutations on increasing the ratio of Αβ42/40 has been highlighted as a signature of neurodegenerative toxicity [3], a systematic analysis of 138 familial PS mutations in vitro [4] revealed that the 42/40 ratio was not consistently elevated and, more tellingly, 90% of these mutations reduced acti…”
BackgroundResultRhomboid distorts lipids to break the viscosity-imposed speed limit of membrane diffusion
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Structure-Based Peptide Inhibitor Design of Amyloid-β Aggregation
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The Links between Cardiovascular Diseases and Alzheimer's Disease
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“Mutations within PSEN1/2 genes that result in γ-secretase complex destabilization, disruption of sequential APP cleavage, and Aβ42 secretion enhancement have been indicated [22-26].”
BackgroundBACE2 distribution in major brain cell types and identification of novel substrates
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Alzheimer’s disease clinical trial update 2019–2021
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Modulation of γ- and β-secretases as early prevention against Alzheimer's disease
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“the ‘E-S complexes’ resulting in premature release of long Aβ peptides (44).”
InfluentialSelf-citationContribution of the Presenilins in the cell biology, structure and function of γ-secretase
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Genetic Phenotypes of Alzheimer’s Disease: Mechanisms and Potential Therapy
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Drug delivery strategies with lipid-based nanoparticles for Alzheimer’s disease treatment
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“Of note, a remarkable correlation between the magnitude of the mutant-induced weakening of the stability of the E-S complexes and the corresponding age of disease onset (Szaruga et al , 2017) places the generation of longer A b ≥ 42 peptides central to AD pathogenesis.”
InfluentialSelf-citationUnraveling the complexity of γ-secretase
Wolfe, M. S. (2020) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2020.01.005 · Cited by 49 · see citing works
“reduction in the carboxypeptidase (aka trimming) function of γ-secretase, rather than in its endoproteolytic function [14, 114, 115, 119, 120].”
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Successive cleavage of β-amyloid precursor protein by γ-secretase
Funamoto, S., Tagami, S., Okochi, M., & Morishima‐Kawashima, M. (2020) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2020.04.002 · Cited by 44 · see citing works
Alternative splicing in a presenilin 2 variant associated with Alzheimer disease
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Modelling neurodegenerative disease using brain organoids
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“…or early onset, are caused by 8 autosomal dominant inherited mutations in amyloid precursor protein (APP) and presenilins 9 (PS) genes, which alter the length and hydrophobicity of the Aβ peptide, triggering the 10 formation of amyloid plaques (Chávez-Gutiérrez et al. 2012; Szaruga et al. 2017).”
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Knockdown of Amyloid Precursor Protein: Biological Consequences and Clinical Opportunities
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Molecular mechanism of substrate recognition and cleavage by human γ-secretase
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Gamma-secretase modulators: a promising route for the treatment of Alzheimer's disease
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Cryo-temperature effects on membrane protein structure and dynamics
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“It is assumed that the consecutive enzyme-substrate complexes become thermodynamically less and less stable as the A β sequence shortens (Szaruga et al, 2017) to 38 , which can all be detected in the extracellular medium (Fig.”
BackgroundMethodInfluentialGDE2-RECK controls ADAM10 α-secretase–mediated cleavage of amyloid precursor protein
Nakamura, M., Li, Y., Choi, B.-R., Matas-Rico, E., Troncoso, J., Takahashi, C., & Sockanathan, S. (2021) · Science Translational Medicine · doi:10.1126/scitranslmed.abe6178 · Cited by 38 · see citing works
“The mechanism that underlies the production of longer A peptides is not well understood, but recent studies implicate enzyme-substrate complex stability in this process (31).”
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Sleep is bi-directionally modified by amyloid beta oligomers
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Role of Microglia in Regulating Cholesterol and Tau Pathology in Alzheimer’s Disease
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Familial Alzheimer mutations stabilize synaptotoxic γ-secretase-substrate complexes
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“42 However, that study did not test E-S complex stability per se, measuring instead the temperature sensitivity of enzyme activity.”
Schultz, S. A., Liu, L., Schultz, A. P., Fitzpatrick, C. D., Levin, R., Bellier, J., Shirzadi, Z., Joseph‐Mathurin, N., Chen, C. D., Benzinger, T. L. S., et al. (2024) · The Lancet Neurology · doi:10.1016/s1474-4422(24)00236-9 · Cited by 34 · see citing works
Self-citationBleomycin modulates amyloid aggregation in β-amyloid and hIAPP
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New RNA-Based Breakthroughs in Alzheimer’s Disease Diagnosis and Therapeutics
Riscado, M., Baptista, B., & de Sousa, F. P. (2021) · Pharmaceutics · doi:10.3390/pharmaceutics13091397 · Cited by 34 · see citing works
“However, γ-secretase modulators [94,95] and γ-secretase stabilizers [96] are still being tested [10,16,83,86].”
BackgroundSignificance of mitochondrial activity in neurogenesis and neurodegenerative diseases
Sun, N., Ozgen, S., Krigman, J., & Zhang, R. (2021) · Neural Regeneration Research · doi:10.4103/1673-5374.322429 · Cited by 34 · see citing works
A novel kit for early diagnosis of Alzheimer’s disease using a fluorescent nanoparticle imaging
Park, J. S., Kim, S. T., Kim, S., Jo, M. G., Choi, M. J., & Kim, M. O. (2019) · Scientific Reports · doi:10.1038/s41598-019-49711-y · Cited by 33 · see citing works
Ten catalytic snapshots of rhomboid intramembrane proteolysis from gate opening to peptide release
Cho, S., Baker, R. P., Ji, M., & Urban, S. (2019) · Nature Structural & Molecular Biology · doi:10.1038/s41594-019-0296-9 · Cited by 33 · see citing works
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Hitzenberger, M., & Zacharias, M. (2019) · Frontiers in Chemistry · doi:10.3389/fchem.2018.00640 · Cited by 32 · see citing works
“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 · see citing works
“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., Sannerud, R., Mondin, M., Poersch, K., Vermeire, W., Paparelli, L., Berlage, C., Koenig, M., Chávez‐Gutiérrez, L., Ulbrich, M. H., et al. (2020) · eLife · doi:10.7554/elife.56679 · Cited by 30 · see citing works
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 30 · see citing works
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 · see citing works
Self-citationPlasma amyloid-β ratios in autosomal dominant Alzheimer’s disease: the influence of genotype
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“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 29 · see citing works
“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 29 · see citing works
“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 · see citing works
Self-citationCai, T., Yonaga, M., & Tomita, T. (2017) · Journal of Neuroscience · doi:10.1523/jneurosci.1628-17.2017 · Cited by 28 · see citing works
“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 · see citing works
Trambauer, J., Fukumori, A., & Steiner, H. (2020) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2020.01.011 · Cited by 28 · see citing works
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 · see citing works
“roborate previous findings on Aβ1–43 [21, 25, 26, 29, 49], suggesting a possible involvement of longer Aβ peptides”
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“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 28 · see citing works
Do, H. N., Devkota, S., Bhattarai, A., Wolfe, M. S., & Miao, Y. (2023) · Communications Biology · doi:10.1038/s42003-023-04539-1 · Cited by 28 · see citing works
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 · see citing works
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 · see citing works
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 26 · see citing works
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 · see citing works
“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 26 · see citing works
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 26 · see citing works
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 · see citing works
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 · see citing works
“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 · see citing works
“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 26 · see citing works
- 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
- 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, 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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