Rho‐associated protein kinase 1 ( ROCK 1) is increased in Alzheimer's disease and ROCK 1 depletion reduces amyloid‐β levels in brain

Alzheimer's disease ( AD ) is the leading cause of dementia and mitigating amyloid‐β (Aβ) levels may serve as a rational therapeutic avenue to slow AD progression. Pharmacologic inhibition of the Rho‐associated protein kinases ( ROCK 1 and ROCK 2) is proposed to curb Aβ levels, and mechanisms that underlie ROCK 2′s effects on Aβ production are defined. How ROCK 1 affects Aβ generation remains a critical barrier. Here, we report that ROCK 1 protein levels were elevated in mild cognitive impairment due to AD (MCI) and AD brains compared to controls. Aβ42 oligomers marginally increased ROCK 1 and ROCK 2 protein levels in neurons but strongly induced phosphorylation of Lim kinase 1 ( LIMK 1), suggesting that Aβ42 activates ROCK s. RNA i depletion of ROCK 1 or ROCK 2 suppressed endogenous Aβ40 production in neurons, and Aβ40 levels were reduced in brains of ROCK 1 heterozygous knock‐out mice compared to wild‐type littermate controls. ROCK 1 knockdown decreased amyloid precursor protein ( APP ), and treatment with bafilomycin accumulated APP levels in neurons depleted of ROCK 1. These observations suggest that reduction of ROCK 1 diminishes Aβ levels by enhancing APP protein degradation. Collectively, these findings support the hypothesis that both ROCK 1 and ROCK 2 are therapeutic targets to combat Aβ production in AD .Mitigating amyloid‐β (Aβ) levels is a rational strategy for Alzheimer's disease ( AD ) treatment, however, therapeutic targets with clinically available drugs are lacking. We hypothesize that Aβ accumulation in mild cognitive impairment because of AD ( MCI ) and AD activates the RhoA/ ROCK pathway which in turn fuels production of Aβ. Escalation of this cycle over the course of many years may contribute to the buildup of amyloid pathology in MCI and/or AD .