A new paradigm for neurotoxicity by FAD mutants of betaAPP: a signaling abnormality.
We have demonstrated that normal betaAPP695 behave as a signaling receptor and indicated that point mutations at V642 create autoactive betaAPP in signal transduction. Cellular expression of those familial Alzheimer's disease-associated mutants causes neuronal cells to undergo apoptotic death; and procedures inhibiting the signal of normal betaAPP block the mutant-induced apoptosis. We have also shown that the mutant-induced death is mediated by intracellular G protein activity but not by secretion of Abeta peptides. Accordingly, the mutant-induced death requires a cytoplasmic domain but not the 41st and 42nd residues of the Abeta region. These studies provide a novel insight that betaAPP may play a normal role as a death receptor and that Alzheimer's disease-relevant abnormality occurred in this function may lead neurons to suicidal degeneration.
Nishimoto
I
I
Department of Pharmacology and Neurosciences, KEIO University School of Medicine, Tokyo, Japan.
D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D019204:GTP-Binding Proteins / Q000502:physiology; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology; D009154:Mutation / Q000235:genetics / Q000502:physiology*; D009410:Nerve Degeneration / Q000235:genetics* / Q000473:pathology*; D053764:Presenilin-1; D015398:Signal Transduction / Q000235:genetics*
D016564:Amyloid beta-Protein Precursor; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D019204:GTP-Binding Proteins