IngentaConnect Proapoptotic Effects of Tau Cleavage Product Generated by Caspase...

Authors: Chung C-W.¹; Song Y-H.¹; Kim I-K.¹; Yoon W-J.²; Ryu B-R.²; Jo D-G.¹; Woo H-N.¹; Kwon Y-K.¹; Kim H-H.¹; Gwag B-J.²; Mook-Jung I-H.²; Jung Y-K.¹

Source: Neurobiology of Disease, Volume 8, Number 1, February 2001 , pp. 162-172(11)

Publisher: Academic Press

Abstract:

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. Delta Tau, 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 Delta Tau in SK-N-BE2(C) cells significantly increased the incidence of cell death. Staurosporine-induced Tau cleavage was blocked by 20 M 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 Delta Tau-induced cell death was augmented by expression of A beta 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. Copyright 2001 Academic Press.

Language: English

Document Type: Research article

Affiliations: 1: Biomedical Brain Research Center, National Institute of Health, Puk-Gu, Kwangju, 500-712, Korea 2: Department of Pharmacology, Ajou University School of Medicine, Suwon, Kyungkido, Korea

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Proapoptotic Effects of Tau Cleavage Product Generated by Caspase-3