机构：[1]Department of Neurology, Neuroscience Institute, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China[2]Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, China[3]National Clinical Research Centre for Neurological Diseases, Beijing Tiantan Hospital Affiliated to Capital Medical University, Beijing, China重点科室诊疗科室神经病学中心神经病学中心首都医科大学附属天坛医院[4]Faculty of Medicine, Neuroscience Research Australia, UNSW Australia, Sydney, New South Wales, Australia[5]Department of Human Anatomy, Histology and Embryology, Institute of Basic Medical Sciences, Neuroscience Center, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, China[6]Department of Geriatrics, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China[7]Institute of Interdisciplinary Science, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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.
基金：
National Natural Science Foundation of ChinaNational Natural Science Foundation of China [81573401, 81671043, 81200842, 81171027, 81501086]; Shanghai Pujiang ProgramShanghai Pujiang Program [15PJ1405400]; Chinese Human Brain Banking Consortium; Shanghai Education Development Foundation; Shuguang Program [16SG15]; Shanghai Municipal Education Commission-Gaofeng Clinical Medicine [20172001]; Chinese Academy of Medical Sciences
第一作者机构：[1]Department of Neurology, Neuroscience Institute, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China[2]Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
通讯作者：
通讯机构：[1]Department of Neurology, Neuroscience Institute, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China[2]Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, China[7]Institute of Interdisciplinary Science, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China[*1]Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.[*2]Department of Neurology, Neuroscience Institute, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
生物