Rho-associated coiled-coil kinase 1 activation mediates amyloid precursor protein site-specific Ser655 phosphorylation and triggers amyloid pathology.
Aging Cell
; 18(5): e13001, 2019 10.
Article
em En
| MEDLINE
| ID: mdl-31287605
ABSTRACT
Rho-associated coiled-coil kinase 1 (ROCK1) is proposed to be implicated in Aß suppression; however, the role for ROCK1 in amyloidogenic metabolism of amyloid precursor protein (APP) to produce Aß was unknown. In the present study, we showed that ROCK1 kinase activity and its APP binding were enhanced in AD brain, resulting in increased ß-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.
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Base de dados:
MEDLINE
Assunto principal:
Fosfosserina
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Peptídeos beta-Amiloides
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Precursor de Proteína beta-Amiloide
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Quinases Associadas a rho
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Doença de Alzheimer
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
China