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Expression of V642 APP mutant causes cellular apoptosis as Alzheimer trait-linked phenotype
T Yamatsuji1, T Okamoto, S Takeda
1Department of Medicine, Harvard Medical School, Charlestown, MA 02129, USA.
Abstract:
APP is a transmembrane precursor of beta-amyloid. In dominantly inherited familial Alzheimer's disease (FAD), point mutations V6421, V642F and V642G have been discovered in APP695. Here we show that expression of these mutants (FAD-APPs) causes a clone of COS cells to undergo apoptosis associated with DNA fragmentation. Apoptosis by the three FAD-APPs was the highest among all possible V642 mutants; normal APP695 had no effect on apoptosis, suggesting that apoptosis by APP mutants in this system is phenotypically linked to the FAD trait. FAD-APP-induced apoptosis was sensitive to bcl-2 and most probably mediated by heteromeric G proteins. This study presents a model system allowing analysis of the mechanism for FAD-APP-induced cytotoxicity.
Insights
Familial Alzheimer's disease mutations in amyloid precursor protein (APP) trigger cell death (apoptosis). This study reveals APP mutants induce apoptosis, offering a model to investigate Alzheimer's disease mechanisms.
Area of Science:
- Neuroscience
- Molecular Biology
- Cell Biology
Background:
- Alzheimer's disease (AD) is a neurodegenerative disorder.
- Amyloid precursor protein (APP) is a key protein implicated in AD pathogenesis.
- Specific mutations in APP are linked to familial forms of Alzheimer's disease (FAD).
Purpose of the Study:
- To investigate the cytotoxic effects of FAD-linked APP mutations.
- To establish a cellular model for studying FAD-APP-induced apoptosis.
- To explore the mechanisms underlying FAD-APP-induced cell death.
Main Methods:
- Expression of wild-type and mutant APP695 in COS cells.
- Assessment of apoptosis using DNA fragmentation assays.
- Analysis of apoptosis sensitivity to bcl-2 and G protein involvement.
Main Results:
- Expression of FAD-linked APP mutants (V642I, V642F, V642G) induced apoptosis in COS cells.
- Apoptosis induction was specific to FAD mutants and not observed with normal APP695.
- FAD-APP-induced apoptosis was sensitive to bcl-2 and likely mediated by G proteins.
Conclusions:
- FAD-linked APP mutations can directly induce cellular apoptosis.
- This cellular system serves as a valuable model for studying FAD pathogenesis.
- The findings suggest a link between APP mutations, apoptosis, and G protein signaling in FAD.