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Cited by 495Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

The mechanism of γ‐Secretase dysfunction in familial Alzheimer disease

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Chávez‐Gutiérrez, Lucía, Bammens, Leen, Benilova, Iryna, Vandersteen, Annelies, Benurwar, Manasi, Borgers, Marianne, Lismont, Sam, Zhou, Lujia +10 more·2012·The EMBO Journal
DOI 10.1038/emboj.2012.79PMC PMC3364747
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Abstract

The mechanisms by which mutations in the presenilins (PSEN) or the amyloid precursor protein (APP) genes cause familial Alzheimer disease (FAD) are controversial. FAD mutations increase the release of amyloid β (Aβ)42 relative to Aβ40 by an unknown, possibly gain-of-toxic-function, mechanism. However, many PSEN mutations paradoxically impair γ-secretase and 'loss-of-function' mechanisms have also been postulated. Here, we use kinetic studies to demonstrate that FAD mutations affect Aβ generation via three different mechanisms, resulting in qualitative changes in the Aβ profiles, which are not limited to Aβ42. Loss of ɛ-cleavage function is not generally observed among FAD mutants. On the other hand, γ-secretase inhibitors used in the clinic appear to block the initial ɛ-cleavage step, but unexpectedly affect more selectively Notch than APP processing, while modulators act as activators of the carboxypeptidase-like (γ) activity. Overall, we provide a coherent explanation for the effect of different FAD mutations, demonstrating the importance of qualitative rather than quantitative changes in the Aβ products, and suggest fundamental improvements for current drug development efforts.

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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 [104]

    The Discussion (page unavailable) says PSEN mutations impair carboxypeptidase-like γ-secretase cleavage and promote premature release of Aβ42 or Aβ43. The Results (page unavailable) report accumulation of longer Aβ precursors, but do not establish faster release of Aβ45 or Aβ46; those species appear in the Introduction as intermediates in a processing model. (LLM, conf=0.84)

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Authors
Chávez‐Gutiérrez, L., Bammens, L., Benilova, I., Vandersteen, A., Benurwar, M., Borgers, M., Lismont, S., Zhou, L., Van Cleynenbreugel, S., Esselmann, H., Wiltfang, J., Serneels, L., Karran, E., Gijsen, H., Schymkowitz, J., Rousseau, F., Broersen, K., & De Strooper, B.
Affiliations
  • KU Leuven (BE)
  • University of Twente (NL)
  • University of Duisburg-Essen (DE)
  • Janssen (Belgium) (BE)
  • Vlaams Instituut voor Biotechnologie (BE)
  • Vrije Universiteit Brussel (BE)
ORCID
Venue
The EMBO Journal
Publisher
Springer Science and Business Media LLC
Published
2012-04-13
Volume
31
Issue
10
Pages
2261-2274
ISSN
  • 0261-4189 (ISSN-L)
  • 1460-2075
DOI
10.1038/emboj.2012.79
PMC
PMC3364747
OpenAlex
W1928655587
Cited by
495
References
7
Citations by year
2026: 9 · 2025: 20 · 2024: 23 · 2023: 27 · 2022: 29 · 2021: 43 · 2020: 39 · 2019: 32 · 2018: 34 · 2017: 32 · 2016: 51 · 2015: 36 · 2014: 42 · 2013: 45 · 2012: 30
FWCI
33.24
Type
journal article
Language
en
Open access
Licence
Locations
  • The EMBO Journal (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
  • UCL Discovery (University College London) (submittedVersion)
  • Lirias (KU Leuven) (submittedVersion)
  • VUBIR (Vrije Universiteit Brussel) (submittedVersion)
Funders
  • Eli Lilly and Company
  • Belgian Federal Science Policy Office
  • Vlaamse regering
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
familial Alzheimer's disease, gamma-secretase, presenilin mutations, amyloid precursor protein, amyloid-beta 42, Aβ40, gamma-secretase inhibitors, gain of toxic function, loss of function, enzyme kinetics
MeSH terms
Alzheimer Disease, Amyloid, Kinetics, Antigens, CD, Cadherins, Receptor, Notch1, Presenilin-1, Amyloid Precursor Protein Secretases, ErbB Receptors, Receptor, ErbB-4

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