Proapoptotic Effects of Tau Cleavage Product Generated by Caspase-3

• Main Authors: Chul-Woong Chung, Yu-Hyun Song, In-Ki Kim, Won-Joo Yoon, Bo-Rum Ryu, Dong-Gyu Jo, Ha-Na Woo, Yun-Kyong Kwon, Hyun-Hee Kim, Byoung-Joo Gwag, In-Hee Mook-Jung, Yong-Keun Jung
• Format: Article
• Language: English
• Published: Elsevier 2001-02-01
• Series: Neurobiology of Disease
• Online Access: http://www.sciencedirect.com/science/article/pii/S0969996100903358

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. ΔTau, 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 ΔTau in SK-N-BE2(C) cells significantly increased the incidence of cell death. Staurosporine-induced Tau cleavage was blocked by 20 μM 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 ΔTau-induced cell death was augmented by expression of Aβ 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.