Expression of V642 APP mutant causes cellular apoptosis as Alzheimer trait-linked phenotype.
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.
Yamatsuji
T
T
Department of Medicine, Harvard Medical School, Charlestown, MA 02129, USA.
Okamoto
T
T
Takeda
S
S
Murayama
Y
Y
Tanaka
N
N
Nishimoto
I
I
D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000595:Amino Acid Sequence; D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000502:physiology*; D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D001483:Base Sequence; D002999:Clone Cells; D004247:DNA / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics; D006801:Humans; D008954:Models, Biological; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010641:Phenotype; D017354:Point Mutation
D016564:Amyloid beta-Protein Precursor; D017931:DNA Primers; D018076:DNA, Complementary; D004247:DNA