The Role Of ROCK1 In The Pathologensis Of Alzheimer’s Disease And Related Mechanism

Alzheimer’s disease(AD)is a progressive neurodegenerative disease and the most common type of clinical dementia.Histopathologically,AD is characterised by extracellular amyloid deposition,neurofibrillary tangles and neuronal loss.Due to the extensive influence of the amyloid hypothesis,the mechanism of Aβ production and clearance have been the hotspot of AD pathogenesis research.Even though its physiological functions remain unclear,APP as a precursor of Aβ,its metabolism and modifications are regulated by many important moleculars.ROCK1 is an important kinase,and previous studies have shown that it was involved in apoptosis,stress fiber formation,cell migration and other physiological processes.Previous studies suggested that ROCK1 involved in the pathogensis of neurodegeration.Therefore,we investigate that the role of ROCK1 in the pathogensis of AD and related mechanisms.Our results suggest that ROCK1 activity is significantly increased in peripheral blood of both AD mouse model and AD patients,indicating that ROCK1 is closely associated with AD.Using methods of proteomics,we found that ROCK1 can regulate the phosphorylation of Ser655 of APP and promote the amyloidogenic pathway,leading to the production of βCTF and Aβ.At the same time,ROCK1 can also promote the formation of autophagosomes and increase the level of autophagy by interacting with its substrate,Beclin1,leading to reduced Aβ secretion and increased cytotoxicity.Therefore,ROCK1 can regulate APP metabolism on two sides,including inducing the production of Aβ and,inhibiting the Aβ secretion and clearance.Therefore,this study shows that ROCK1 plays an important role in the pathologensis of AD.ROCK1 can be a potential target for AD therapies in future.