Rho-associated coiled-coil kinase 1 activation mediates amyloid precursor protein site-specific Ser655 phosphorylation and triggers amyloid pathology.

Rho-associated coiled-coil kinase 1 (ROCK1) is proposed to be implicated in A beta suppression; however, the role for ROCK1 in amyloidogenic metabolism of amyloid precursor protein (APP) to produce A beta was unknown. In the present study, we showed that ROCK1 kinase activity and its APP binding were enhanced in AD brain, resulting in increased beta-secretase cleavage of APP. Furthermore, we firstly confirmed that APP served as a substrate for ROCK1 and its major phosphorylation site was located at Ser655. The increased level of APP Ser655 phosphorylation was observed in the brain of APP/PS1 mice and AD patients compared to controls. Moreover, blockade of APP Ser655 phosphorylation, or inhibition of ROCK1 activity with either shRNA knockdown or Y-27632, ameliorated amyloid pathology and improved learning and memory in APP/PS1 mice. These findings suggest that activated ROCK1 targets APP Ser655 phosphorylation, which promotes amyloid processing and pathology. Inhibition of ROCK1 could be a potential therapeutic approach for AD.