title: ROCK1 Is Associated with Alzheimer's Disease-Specific Plaques, as well as Enhances Autophagosome Formation But not Autophagic Aβ Clearance.
abstract: Alzheimer's disease (AD) is the most prevalent form of late-life dementia in the population, characterized by amyloid plaque formation and increased tau deposition, which is modulated by Rho-associated coiled-coil kinase 1 (ROCK1). In this study, we further analyze whether ROCK1 regulates the metabolism of amyloid precursor protein (APP). We show that ROCK1 is colocalized with mature amyloid-β (Aβ) plaques in patients with AD, in that ROCK1 enhances the amyloidogenic pathway, and that ROCK1 mediated autophagy enhances the intracellular buildup of Aβ in a cell model of AD (confirmed by increased ROCK1 and decreased Beclin 1 protein levels, with neuronal autophagosome accumulation in prefrontal cortex of AD APP/PS1 mouse model).In vitroover-expression of ROCK1 leads to a decrease in Aβ secretion and an increase in the expression of autophagy-related molecules. ROCK1 interacts with Beclin1, an autophagy initiator, and enhances the intracellular accumulation of Aβ. Reciprocally, overexpression of APP/Aβ promotes ROCK1 expression. Our data suggest ROCK1 participates in regulating Aβ secretion, APP shedding and autophagosome accumulation, and that ROCK1, rather than other kinases, is more likely to be a targetable enzyme for AD therapy.
authors.affiliation: Department of Neurology and Neuroscience Institute, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine Shanghai, China.
authors.forename: Yong-Bo
authors.initials: YB
authors.lastname: Hu
authors.affiliation: Department of Neurology and Neuroscience Institute, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine Shanghai, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zou
authors.affiliation: Neuroscience Research Australia and Faculty of Medicine, University of New South Wales (UNSW) Sydney, NSW, Australia.
authors.forename: Yue
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Research Laboratory of Cell Regulation, School of Medicine, Shanghai Jiao Tong University Shanghai, China.
authors.forename: Yong-Fang
authors.initials: YF
authors.lastname: Zhang
authors.affiliation: Neuroscience Research Australia and Faculty of Medicine, University of New South Wales (UNSW) Sydney, NSW, Australia.
authors.forename: Guinevere F
authors.initials: GF
authors.lastname: Lourenco
authors.affiliation: Department of Neurology and Neuroscience Institute, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine Shanghai, China.
authors.forename: Sheng-Di
authors.initials: SD
authors.lastname: Chen
authors.affiliation: Neuroscience Research Australia and Faculty of Medicine, University of New South Wales (UNSW) Sydney, NSW, Australia.
authors.forename: Glenda M
authors.initials: GM
authors.lastname: Halliday
authors.affiliation: Department of Neurology and Neuroscience Institute, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine Shanghai, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Wang
authors.affiliation: Department of Neurology and Neuroscience Institute, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine Shanghai, China.
authors.forename: Ru-Jing
authors.initials: RJ
authors.lastname: Ren
keywords: Alzheimer’s disease; Aβ; Beclin1; ROCK1; autophagy