Cited by 223Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Pathogenic APP mutations near the gamma-secretase cleavage site differentially affect Abeta secretion and APP C-terminal fragment stability

De Jonghe, C.·2001·Human Molecular Genetics

Abstract

Release of amyloid beta (Abeta) from the amyloid precursor protein (APP) requires cleavages by beta- and gamma-secretases and plays a crucial role in Alzheimer's disease (AD) pathogenesis. Missense mutations in the APP gene causing familial AD are clustered around the beta-, alpha- and particular gamma-secretase cleavage sites. We systematically compare in primary neurons the effect on APP processing of a series of clinical APP mutations (two of which not characterized before) located in close proximity to the gamma-secretase cleavage site. We confirm and extend previous observations showing that all these mutations (T714I, V715M, V715A, I716V, V717I and V717L) affect gamma-secretase cleavage causing an increased relative ratio of Abeta42 to Abeta40. Taking advantage of these extended series of APP mutations we were able to demonstrate an inverse correlation between these ratios and the age at onset of the disease in the different families. In addition, a subset of mutations caused the accumulation of APP C-terminal fragments indicating that these mutations also influence the stability of APP C-terminal fragments. However, it is unlikely that these fragments contribute significantly to the disease process.

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Crossref · 10.1093/hmg/10.16.1665

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Authors
De Jonghe, C.
Venue
Human Molecular Genetics
Published
2001-08-01
Volume
10
Issue
16
Pages
1665-1671
ISSN
  • 0964-6906 (ISSN-L)
  • 1460-2083
OpenAlex
W2159237576
Cited by
223
References
36
Citations by year
2026: 1 · 2025: 11 · 2024: 11 · 2023: 9 · 2022: 10 · 2021: 10 · 2020: 16 · 2019: 13 · 2018: 8 · 2017: 12 · 2016: 5 · 2015: 8 · 2014: 18 · 2013: 9 · 2012: 6
FWCI
3.54
Type
journal article
Language
en
Open access
closed
Locations
  • Human Molecular Genetics (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Fonds Wetenschappelijk Onderzoek
  • 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
amyloid precursor protein, APP mutations, amyloid-beta secretion, Aβ42/Aβ40 ratio, APP C-terminal fragments, familial Alzheimer's disease, primary neurons, age of onset
MeSH terms
Animals, Binding Sites, Cells, Cultured, Electrophoresis, Polyacrylamide Gel, Humans, Mutation, Neurons, Peptide Fragments, Endopeptidases, Precipitin Tests, Transduction, Genetic, Amyloid beta-Peptides, Aspartic Acid Endopeptidases, Amyloid beta-Protein Precursor, Mice, Amyloid Precursor Protein Secretases

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