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Cited by 155Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Qualitative changes in human γ-secretase underlie familial Alzheimer’s disease

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Szaruga, Maria, Veugelen, Sarah, Benurwar, Manasi, Lismont, Sam, Sepulveda-Falla, Diego, Lleo, Alberto, Ryan, Natalie S., Lashley, Tammaryn +5 more·2015·Journal of Experimental Medicine
DOI 10.1084/jem.20150892PMC PMC4647268
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Abstract

Presenilin (PSEN) pathogenic mutations cause familial Alzheimer’s disease (AD [FAD]) in an autosomal-dominant manner. The extent to which the healthy and diseased alleles influence each other to cause neurodegeneration remains unclear. In this study, we assessed γ-secretase activity in brain samples from 15 nondemented subjects, 22 FAD patients harboring nine different mutations in PSEN1, and 11 sporadic AD (SAD) patients. FAD and control brain samples had similar overall γ-secretase activity levels, and therefore, loss of overall (endopeptidase) γ-secretase function cannot be an essential part of the pathogenic mechanism. In contrast, impaired carboxypeptidase-like activity (γ-secretase dysfunction) is a constant feature in all FAD brains. Significantly, we demonstrate that pharmacological activation of the carboxypeptidase-like γ-secretase activity with γ-secretase modulators alleviates the mutant PSEN pathogenic effects. Most SAD cases display normal endo- and carboxypeptidase-like γ-secretase activities. However and interestingly, a few SAD patient samples display γ-secretase dysfunction, suggesting that γ-secretase may play a role in some SAD cases. In conclusion, our study highlights qualitative shifts in amyloid-β (Aβ) profiles as the common denominator in FAD and supports a model in which the healthy allele contributes with normal Aβ products and the diseased allele generates longer aggregation-prone peptides that act as seeds inducing toxic amyloid conformations.

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  • PSEN1 mutations increase the faster release of long Aβ peptide species due to altered carboxypeptidase-like γ-secretase activity that increases the proportion of Aβ42, Aβ43, and even longer Aβ peptide species.

    “PSEN1 mutations increase the faster release of long A 𝛃 peptide species due to altered carboxypeptidase-like 𝛄 -secretase activity that increases the proportion of A 𝛃 42, A 𝛃 43, and even longer A 𝛃 peptide species (A 𝛃 45, A 𝛃 46) (104, 172, 489, 572).”

    From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [572]

    The Results and Discussion section on carboxypeptidase-like efficiency reports reduced efficiency in PSEN1-mutant FAD brains and suggests a shift toward longer Aβ peptides. The paper discusses Aβ43, Aβ45, and Aβ46, but does not establish faster release of those peptides; it also finds no increase in Aβ42 production in most FAD brain samples. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • The ratio of Aβ42:Aβ40 is altered in most, but not all, PSEN1 mutation carriers.

    “Moreover, the ratio of A 𝛃 42:A 𝛃 40 is altered in most, but not all, PSEN1 mutations carriers (572), and the significance of the altered ratio is not well understood.”

    From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [572]

  • Previous studies of our group have identified molecular differences between SAD and FAD in addition to divergences in clinical manifestations.

    “Previous studies of our group have identified molecular differences between SAD and FAD [55, 56, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79] in addition to divergences in the clinical manifestations [55, 56].”

    From Gliovascular alterations in sporadic and familial Alzheimer's disease: <scp><i>APOE3</i></scp> Christchurch homozygote glioprotection (2023) · cites this paper as [76]

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References 38 · Cited by 155

Research works printed but not linked: 35

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Authors
Szaruga, M., Veugelen, S., Benurwar, M., Lismont, S., Sepulveda-Falla, D., Lleo, A., Ryan, N. S., Lashley, T., Fox, N. C., Murayama, S., Gijsen, H., De Strooper, B., & Chávez-Gutiérrez, L.
Affiliations
  • VIB Center for the Biology of Disease, University of Leuven (KU Leuven), 3000 Leuven, Belgium 1
  • KU Leuven (BE)
  • Institut für Neuropathologie, Universitätsklinikum Hamburg-Eppendorf, 20246 Hamburg, Germany 3
  • Unidad de Memoria, Departamento de Neurología, Institut d’Investigacions Biomèdiques Sant Pau, Hospital de Sant Pau, 08025 Barcelona, Spain 5
  • UCL Queen Square Institute of Neurology (GB)
  • National Hospital for Neurology and Neurosurgery (GB)
  • Tokyo Metropolitan Institute of Gerontology (JP)
  • Janssen (Belgium) (BE)
ORCID
Venue
Journal of Experimental Medicine
Publisher
Rockefeller University Press
Published
2015-10-19
Volume
212
Issue
12
Pages
2003-2013
ISSN
  • 0022-1007 (ISSN-L)
  • 1540-9538
DOI
10.1084/jem.20150892
PMC
PMC4647268
OpenAlex
W2180506828
Cited by
155
References
38
Citations by year
2026: 1 · 2025: 8 · 2024: 10 · 2023: 13 · 2022: 16 · 2021: 17 · 2020: 19 · 2019: 18 · 2018: 15 · 2017: 19 · 2016: 18 · 2015: 1
FWCI
13.01
Type
journal article
Language
en
Open access
Locations
  • The Journal of Experimental Medicine (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
  • Dipòsit Digital de Documents de la UAB (Universitat Autònoma de Barcelona) (submittedVersion, cc-by-nc-sa)
  • UCL Discovery (University College London) (submittedVersion)
  • Lirias (submittedVersion)
Funders
  • Alzheimer's Society
  • National Institute for Health and Care Research (NF-SI-0513-10134, NF-SI-0508-10123)
  • Belgian Federal Science Policy Office
  • KU Leuven
  • Universidad de Antioquia
  • Vlaamse regering
  • Medical Research Council
  • Instituto de Salud Carlos III
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
gamma-secretase, familial Alzheimer's disease, presenilin 1 mutations, endopeptidase activity, γ-secretase modulators, amyloid-beta, sporadic Alzheimer's disease, amyloid fibril formation, seed propagation, autosomal dominant inheritance, neurodegeneration
MeSH terms
Adult, Aged, Alzheimer Disease, Amyloid, Animals, Brain, Carboxypeptidases, Cells, Cultured, Female, Humans, Male, Middle Aged, Mutation, Blotting, Western, Amyloid beta-Protein Precursor, Mice, Knockout, Presenilin-1, Amyloid Precursor Protein Secretases

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