Amyloid beta peptide-induced cerebral neuronal loss is mediated by caspase-3 in vivo.
Amyloid beta peptide (A beta) is widely believed to play a central and etiological role in Alzheimer disease (AD). A beta has been shown to have cytotoxic effects in neural cells, although the mechanism by which it does this is still unclear. To examine the involvement of the apoptotic cascade in A beta-induced cell death, we used mice deficient in caspase-3 (CPP 32), a key protease in this cascade. We microinjected A beta(1-40) into hippocampal regions of the brains of adult mice because AD is an adult-onset disease. We found significant cellular loss in the hippocampal regions of wild-type mice and dramatic rescue of neuronal cell death in caspase-3-deficient mice, with a gene dosage effect. In addition to adult mice, we observed little A beta-induced death of cultured neurons prepared from fetal brains of caspase-3-deficient mice but did observe death of such neurons from wild-type mice. The difference in A beta-induced neuronal death between wild-type and caspase-3-deficient mice was highly significant, indicating that A beta-induced neuronal death is mediated in vivo as well as in vitro by the caspase-3 apoptotic cascade.
Takuma
Hiroshi
H
Department of Neuroscience, Graduate School of Medicine, Osaka City University, Osaka, Japan.
Tomiyama
Takami
T
Kuida
Keisuke
K
Mori
Hiroshi
H
D000544:Alzheimer Disease / Q000201:enzymology* / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D053148:Caspase 3; D020169:Caspases / Q000172:deficiency* / Q000235:genetics; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005333:Fetus; D018628:Gene Dosage; D006624:Hippocampus / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D009410:Nerve Degeneration / Q000139:chemically induced / Q000201:enzymology* / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D010446:Peptide Fragments / Q000378:metabolism / Q000633:toxicity; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases