c-Abl tyrosine kinase modulates tau pathology and Cdk5 phosphorylation in AD transgenic mice.
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-β-peptide (Aβ) activates c-Abl. Herein we show that c-Abl participates in Aβ-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 Aβ 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 Aβ promotes tau phosphorylation through Tyr15 phosphorylation-mediated Cdk5 activation.
Cancino
Gonzalo I
GI
Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Av. Alameda 340, Santiago, Chile. gcancino@puc.cl
Perez de Arce
Karen
K
Castro
Paula U
PU
Toledo
Enrique M
EM
von Bernhardi
Rommy
R
Alvarez
Alejandra R
AR
D000544:Alzheimer Disease / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology*; D016564:Amyloid beta-Protein Precursor / Q000502:physiology; D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006624:Hippocampus / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D010766:Phosphorylation / Q000502:physiology; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016875:tau Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000633:toxicity*
D016564:Amyloid beta-Protein Precursor; C054369:MAPT protein, human; D016875:tau Proteins; D016315:Proto-Oncogene Proteins c-abl