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J. Biol. Chem., Vol. 279, Issue 52, 54716-54723, December 24, 2004

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Glycogen Synthase Kinase 3 Induces Caspase-cleaved Tau Aggregation in Situ^*

Jae-Hyeon Cho and Gail V. W. Johnson

From the Department of Psychiatry, University of Alabama at Birmingham, Birmingham, Alabama 35294-0017

Tau is a substrate of caspases, and caspase-cleaved tau has been detected in Alzheimer's disease brain but not in control brain. Furthermore, in vitro studies have revealed that caspase-cleaved tau is more fibrillogenic than full-length tau. Considering these previous findings, the purpose of this study was to determine how the caspase cleavage of tau affected tau function and aggregation in a cell model system. The effects of glycogen synthase kinase 3 (GSK3), a well established tau kinase, on these processes also were examined. Tau or tau that had been truncated at Asp-421 to mimic caspase cleavage (Tau-D421) was transfected into cells with or without GSK3, and phosphorylation, microtubule binding, and tau aggregation were examined. Tau-D421 was not as efficiently phosphorylated by GSK3 as full-length tau. Tau-D421 efficiently bound microtubules, and in contrast to the full-length tau, co-expression with GSK3 did not result in a reduction in the ability of Tau-D421 to bind microtubules. In the absence of GSK3, neither Tau-D421 nor full-length tau formed Sarkosyl-insoluble inclusions. However, in the presence of GSK3, Tau-D421, but not full-length tau, was present in the Sarkosyl-insoluble fraction and formed thioflavin-S-positive inclusions in the cell. Nonetheless, co-expression of GSK3 and Tau-D421 did not result in an enhancement of cell death. These data suggest that a combination of phosphorylation events and caspase activation contribute to the tau oligomerization process in Alzheimer's disease, with GSK3-mediated tau phosphorylation preceding caspase cleavage.

Received for publication, March 25, 2004 , and in revised form, August 17, 2004.

^* This work was supported by National Institutes of Health Grant NS35060 and a grant from the Alzheimer's Disease Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by a fellowship from the John Douglas French Alzheimer's Foundation.

To whom correspondence should be addressed: Dept. of Psychiatry, 1720 7th Ave. S., SC1061, University of Alabama at Birmingham, School of Medicine, Birmingham, AL 35294-0017. Tel.: 205-934-2465; Fax: 205-934-3709; E-mail: gvwj{at}uab.edu.

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