Proapoptotic effects of tau cleavage product generated by caspase-3.
Using an in vitro translation assay to screen a human brain cDNA library, we isolated the microtubule-associated protein Tau and determined it to be a caspase-3 substrate whose C-terminal cleavage occurred during neuronal apoptosis. DeltaTau, the 50-kDa cleavage product, was detected by Western blot in apoptotic cortical cells probed with anti-PHF-1 and anti-Tau-5 antibodies, but not anti-T-46 antibody which recognizes the C-terminus. Overexpression of DeltaTau in SK-N-BE2(C) cells significantly increased the incidence of cell death. Staurosporine-induced Tau cleavage was blocked by 20 microM z-Asp-Glu-Val-Asp-chloromethylketone, a caspase-3 inhibitor, and in vitro, Tau was selectively cleaved by caspase-3 or calpain, a calcium-activated protease, but not by caspases-1, -8, or -9. (D421E)-Tau, a mutant in which Asp421 was replaced with a Glu, was resistant to cleavage by caspase-3 and tended to suppress staurosporine-induced cell death more efficiently than did wild-type Tau in both transient and stable expression systems. Finally, the incidence of DeltaTau-induced cell death was augmented by expression of Abeta precursor protein (APP) or Swedish APP mutant. Taken together, these results suggest that the caspase-3 cleavage product of Tau may contribute to the progression of neuronal cell death in Alzheimer's disease.
Chung
C W
CW
Department of Life Science, Kwangju Institute of Science and Technology, and Biomedical Brain Research Center, National Institute of Health, Puk-Gu, Kwangju, 500-712, Korea.
Song
Y H
YH
Kim
I K
IK
Yoon
W J
WJ
Ryu
B R
BR
Jo
D G
DG
Woo
H N
HN
Kwon
Y K
YK
Kim
H H
HH
Gwag
B J
BJ
Mook-Jung
I H
IH
Jung
Y K
YK
D016564:Amyloid beta-Protein Precursor / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007202:Indicators and Reagents; D010446:Peptide Fragments / Q000235:genetics / Q000633:toxicity; D010957:Plasmids / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology; D014162:Transfection; D001616:beta-Galactosidase / Q000096:biosynthesis; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism* / Q000633:toxicity*
D016564:Amyloid beta-Protein Precursor; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D010446:Peptide Fragments; D011994:Recombinant Proteins; D016875:tau Proteins; D001616:beta-Galactosidase; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases