Multiple mechanisms underlie neurotoxicity by different types of Alzheimer's disease mutations of amyloid precursor protein.
We examined a neuronal cell system in which single-cell expression of either familial Alzheimer's disease (FAD) gene V642I-APP or K595N/M596L-APP (NL-APP) in an inducible plasmid was controlled without affecting transfection efficiency. This system revealed that (i) low expression of both mutants exerted toxicity sensitive to both Ac-DEVD-CHO (DEVD) and glutathione ethyl ester (GEE), whereas wild-type APP (wtAPP) only at higher expression levels caused GEE/DEVD-resistant death to lesser degrees; (ii) toxicity by the V642I mutation was entirely GEE/DEVD sensitive; and (iii) toxicity by higher expression of NL-APP was GEE/DEVD resistant. The GEE/DEVD-sensitive death was sensitive to pertussis toxin and was due to G(o)-interacting His(657)-Lys(676) domain. The GEE/DEVD-resistant death was due to C-terminal Met(677)-Asn(695). APP mutants lacking either domain unraveled elaborate intracellular cross-talk between these domains. E618Q-APP, responsible for non-AD type of a human disease, only exerted GEE/DEVD-resistant death at higher expression. Therefore, (i) different FAD mutations in APP cause neuronal cell death through different cytoplasmic domains via different sets of mechanisms; (ii) expression levels of FAD genes are critical in activating specific death mechanisms; and (iii) toxicity by low expression of both mutants most likely reflects the pathogenetic mechanism of FAD.
Department of Pharmacology, KEIO University School of Medicine, Shinanomachi, Tokyo 160, Japan.
Y
Y
Hashimoto
T
T
Niikura
Y
Y
Ito
I
I
Nishimoto
D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000502:physiology*; D001483:Base Sequence; D016923:Cell Death / Q000187:drug effects; D017931:DNA Primers; D006801:Humans; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D009474:Neurons / Q000473:pathology; D014810:Vitamin E / Q000494:pharmacology
D016564:Amyloid beta-Protein Precursor; D017931:DNA Primers; D014810:Vitamin E