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Proapoptotic effects of tau cleavage product generated by caspase-3.

Authors
Chung, CW; Song, YH; Kim, IK; Yoon, WJ; Ryu, BR; Jo, DG; Woo, HN; Kwon, YK; Kim, HH; Gwag, BJ; Mook-Jung, IH; Jung, YK
Citation
Neurobiology of disease, 8(1):162-172, 2001
Journal Title
Neurobiology of disease
ISSN
0969-99611095-953X
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. 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.
MeSH terms
Amyloid beta-Protein Precursor/pharmacologyApoptosis/drug effects*Blotting, WesternCaspase 3Caspases/antagonists & inhibitorsCaspases/metabolism*Cell LineCells, CulturedEnzyme Inhibitors/pharmacologyHumansIndicators and ReagentsPeptide Fragments/geneticsPeptide Fragments/toxicityPlasmids/geneticsRecombinant Proteins/pharmacologyTransfectionbeta-Galactosidase/biosynthesistau Proteins/geneticstau Proteins/metabolism*tau Proteins/toxicity*
DOI
10.1006/nbdi.2000.0335
PMID
11162250
Appears in Collections:
Journal Papers > Research Organization > Brain Disease Research Center
Journal Papers > School of Medicine / Graduate School of Medicine > Pharmacology
AJOU Authors
곽, 병주묵, 인희
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