Mutations in APP have independent effects on Aβ and CTFγ generation

Hecimovic, Silva; Wang, Jun; Dolios, Georgia; Martinez, Maribel; Wang, Rong; Goate, Alison M.

doi:10.1016/j.nbd.2004.04.018

Cited by 70Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Mutations in APP have independent effects on Aβ and CTFγ generation

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Hecimovic, Silva, Wang, Jun, Dolios, Georgia, Martinez, Maribel, Wang, Rong, Goate, Alison M.·2004·Neurobiology of Disease

DOI 10.1016/j.nbd.2004.04.018

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Abstract

Understanding the molecular mechanism of beta-amyloid (Abeta) generation is crucial for Alzheimer's disease pathogenesis as well as for normal APP function. The transmembrane domain (TM) of APP appears to undergo presenilin-dependent gamma-secretase cleavage at two topologically distinct sites: a site in the middle of the TM domain that is crucial for the generation of Abeta-peptides, and a site close to the cytoplasmic border (S3-like/epsilon site) of the TM domain that leads to production of the APP intracellular domain (CTFgamma/AICD). We demonstrate that, in contrast to the unique effect of familial Alzheimer's disease (FAD) mutations in APP on Abeta42 production, some but not all FAD mutations also affect CTFgamma generation. Furthermore, changes in total CTFgamma levels do not correlate with either an increase or a decrease of any Abeta species, and inhibition of Abeta-peptide formation starting from position +1 (Abeta1-x) does not affect CTFgamma production. These results suggest that cleavage at the gamma40/42- and the S3-like sites can be dissociated, and that APP signaling and Abeta production are not tightly linked.

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All autosomal dominant mutations associated with rare familial early onset AD in APP and presenilin 1 and 2 increase the proportion of Aβ42 to Aβ40 peptides.
“all autosomal dominant mutations associated with rare familial forms of early onset AD in the amyloid precursor protein (APP) and presenilin (PS) 1 and 2 were shown to increase the proportion of Aβ42 to Aβ40 peptides.”
From Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease (2010) · cites this paper as [71]

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Authors: Hecimovic, S., Wang, J., Dolios, G., Martinez, M., Wang, R., & Goate, A. M.
Affiliations: Washington University in St. Louis (US)
Icahn School of Medicine at Mount Sinai (US)
Corresponding author: Goate, Alison M.
ORCID: Hecimovic, Silva
Wang, Jun
Dolios, Georgia
Wang, Rong
Goate, Alison M.
Venue: Neurobiology of Disease
Publisher: Elsevier BV
Published: 2004-11
Volume: 17
Issue: 2
Pages: 205-218
ISSN: 0969-9961 (ISSN-L)
DOI: 10.1016/j.nbd.2004.04.018
OpenAlex: W2085469435
Cited by: 70
References: 57
Citations by year: 2026: 1 · 2025: 5 · 2024: 1 · 2022: 4 · 2021: 1 · 2019: 1 · 2017: 2 · 2016: 1 · 2015: 3 · 2014: 4 · 2013: 3 · 2012: 3
FWCI: 3.49
Type: journal article
Language: en
Open access: green
doaj.org
Licence: cc-by-sa
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Neurobiology of Disease (publishedVersion)
PubMed (publishedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders: National Institute on Aging (P01AG010491, AG10491, AG17050, R01AG017050)
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: APP mutations, gamma-secretase, APP intracellular domain, familial Alzheimer's disease, amyloid-beta 42, transmembrane domain, Alzheimer's disease pathogenesis
MeSH terms: Alzheimer Disease, Cell Line, Humans, Mutation, Peptide Fragments, Endopeptidases, Amyloid beta-Peptides, Aspartic Acid Endopeptidases, Amyloid beta-Protein Precursor, Protein Transport, Amyloid Precursor Protein Secretases

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Mutations in APP have independent effects on Aβ and CTFγ generation

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