c-Abl tyrosine kinase modulates tau pathology and Cdk5 phosphorylation in AD transgenic mice

Abstract
The c-Abl tyrosine kinase is an important link in signal transduction pathways that promote cytoskeletal rearrangement and apoptotic signalling. We have previously shown that amyloid-beta-peptide (A beta) activates c-Abl. Herein we show that c-Abl participates in A beta-induced tau phosphorylation through Cdk5 activation. We found that intraperitoneal administration of STI571, a specific inhibitor for c-Abl kinase, decreased tau phosphorylation in the APPswe/PSEN1 Delta E9 transgenic mouse brain. In addition, when neurons were treated with A beta we observed: (i) an increase in active c-Abl and tau phosphorylation, (ii) the prevention of tau phosphorylation by STI571 and (iii) the inhibition of c-Abl expression by shRNA, as well as the expression of a c-Abl kinase death mutant, decreased AT8 and PHF1 signals. Furthermore, the increase of c-Abl was associated with Tyr15 phosphorylation of Cdk5 and its association with c-Abl. Brains from APPswe/PSEN1 Delta E9 mice showed higher levels of c-Abl and phospho-Cdk5 than wild-type mice. Moreover, STI571 treatment decreased the phospho-Cdk5 levels. Together, the evidence suggests that activation of c-Abl by A beta promotes tau phosphorylation through Tyr15 phosphorylation-mediated Cdk5 activation. (C) 2009 Elsevier Inc. All rights reserved.
Description
Keywords
c-Abl, Cdk5, Neurotoxicity, Tau phosphorylation
Citation
Cancino, Gonzalo, Perez de Arce, Karen, Castro U, Paula, Toledo M, Enrique, Von Benhardi, Rommy, Alvarez, Alejandra. c-Abl tyrosine kinase modulates tau pathology and Cdk5 phosphorylation in AD transgenic mice . Neurobiology Of Aging. 2009;xx(xx):x-x.