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c-Abl tyrosine kinase modulates tau pathology and Cdk5 phosphorylation in AD transgenic mice.
Cancino, Gonzalo I; Perez de Arce, Karen; Castro, Paula U; Toledo, Enrique M; von Bernhardi, Rommy; Alvarez, Alejandra R.
Afiliação
  • Cancino GI; Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Av. Alameda 340, Santiago, Chile. gcancino@puc.cl
Neurobiol Aging ; 32(7): 1249-61, 2011 Jul.
Article em En | MEDLINE | ID: mdl-19700222
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-ß-peptide (Aß) activates c-Abl. Herein we show that c-Abl participates in Aß-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/PSEN1ΔE9 transgenic mouse brain. In addition, when neurons were treated with Aß 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/PSEN1ΔE9 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 Aß promotes tau phosphorylation through Tyr15 phosphorylation-mediated Cdk5 activation.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteínas Proto-Oncogênicas c-abl / Proteínas tau / Doença de Alzheimer / Hipocampo Limite: Animals / Humans Idioma: En Revista: Neurobiol Aging Ano de publicação: 2011 Tipo de documento: Article País de afiliação: Chile País de publicação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteínas Proto-Oncogênicas c-abl / Proteínas tau / Doença de Alzheimer / Hipocampo Limite: Animals / Humans Idioma: En Revista: Neurobiol Aging Ano de publicação: 2011 Tipo de documento: Article País de afiliação: Chile País de publicação: Estados Unidos