c-Abl tyrosine kinase modulates tau pathology and Cdk5 phosphorylation in AD transgenic mice.
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteínas Proto-Oncogênicas c-abl
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Proteínas tau
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Doença de Alzheimer
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Hipocampo
Limite:
Animals
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Humans
Idioma:
En
Revista:
Neurobiol Aging
Ano de publicação:
2011
Tipo de documento:
Article
País de afiliação:
Chile
País de publicação:
Estados Unidos