Caspase-3-mediated cleavage of PHF-1 tau during apoptosis irrespective of excitotoxicity and oxidative stress: an implication to Alzheimer's disease.
Excitotoxicity, oxidative stress, and apoptosis have been recognized as routes to neuronal death in various neurological diseases. We examined the possibility that PHF-1 tau, a substrate for various proteases, would be selectively cleaved depending upon routes of neuronal death. Cleavage form of PHF-1 tau was not observed in cortical cell cultures exposed to excitotoxins or oxidative stress that cause neuronal cell necrosis. PHF-1 tau was cleaved within 8 h following exposure of cortical cell cultures to apoptosis-inducing agents. This cleavage was blocked by inclusion of zDEVD-fmk, an inhibitor of caspase-3, and accompanied by activation of caspase-3. Levels and cleavage of PHF-1 tau were markedly increased in AD brain compared with control. Moreover, PHF-1 tau and active caspase-3 were colocalized mostly in tangle-bearing neurons. The current findings suggest that PHF-1 tau is cleaved by caspase-3 during apoptosis and neurodegenerative process in AD.
Kang
Hyo Jung
HJ
Department of Neuroscience, Ajou University School of Medicine, Suwon, Kyungkido, Korea.
Yoon
Won Joo
WJ
Moon
Gyeong Joon
GJ
Kim
Doo Yeon
DY
Sohn
Seonghyang
S
Kwon
Hyuk Jae
HJ
Gwag
Byoung Joo
BJ
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism*; D017209:Apoptosis / Q000502:physiology*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D049109:Cell Proliferation; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D018384:Oxidative Stress / Q000502:physiology*; D013379:Substrate Specificity; D016875:tau Proteins / Q000276:immunology / Q000378:metabolism*
D000911:Antibodies, Monoclonal; C085349:PHF-1 monoclonal antibody; D016875:tau Proteins; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases