Rho‐associated protein kinase 1 (ROCK1) is increased in Alzheimer's disease and ROCK1 depletion reduces amyloid‐β levels in brain

Abstract

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 (ROCK1 and ROCK2) is proposed to curb Aβ levels, and mechanisms that underlie ROCK2’s effects on Aβ production are defined. How ROCK1 affects Aβ generation remains a critical barrier. Here, we report that ROCK1 protein levels were elevated in mild cognitive impairment due to AD (MCI) and AD brains compared to controls. Aβ42 oligomers marginally increased ROCK1 and ROCK2 protein levels in neurons but strongly induced phosphorylation of Lim kinase 1 (LIMK1), suggesting that Aβ42 activates ROCKs. RNAi depletion of ROCK1 or ROCK2 suppressed endogenous Aβ40 production in neurons, and Aβ40 levels were reduced in brains of ROCK1 heterozygous knock-out mice compared to wild-type littermate controls. ROCK1 knockdown decreased amyloid precursor protein (APP), and treatment with bafilomycin accumulated APP levels in neurons depleted of ROCK1. These observations suggest that reduction of ROCK1 diminishes Aβ levels by enhancing APP protein degradation. Collectively, these findings support the hypothesis that both ROCK1 and ROCK2 are therapeutic targets to combat Aβ production in AD.

ROCK1 Is Associated with Alzheimer’s Disease-Specific Plaques, as well as Enhances Autophagosome Formation But not Autophagic Aβ Clearance

“…APP shedding is directly mediated by α- and β-secretase generating either non-amyloidogenic (sAPPα) or amyloidogenic fragments (Tang, 2005). Our data show that ROCK1 activation enhances the amyloidogenic pathway, consistent with recent data (Henderson et al, 2016). However, we demonstrate that ROCK1 decreased sAPPα shedding in cultured cells, but also reduced rather than increased Aβ secretion from the cells, suggesting that ROCK1 may also play a role in Aβ secretion at the plasma membrane (potentially associated with the aberrant phosphorylation of Aβ, see above).…”

“…Two constitutively-expressed ROCK enzymes have been identified—ROCK1 and ROCK2 that share 92% homology in their kinase domain and differ most in their regulatory domains and subcellular localization (Ishizaki et al, 1997; Shi et al, 2013; Chong et al, 2016). Recent studies show that ROCK1 modulates the shedding of the α-secretase-cleaved soluble APP ectodomain (sAPPα) from cultured cells, and that ROCK1 depletion reduces the levels of Aβ (Herskowitz et al, 2013; Henderson et al, 2016). The buildup of internal Aβ rather than its external deposition is associated with neuronal loss in APP/PS1 knock-in mice suggesting externalization of cellular Aβ is protective (Christensen et al, 2008).…”

“…ROCK1 phosphorylation of Beclin1 is the critical regulator for stress-induced autophagy (Gurkar et al, 2013). A reduction in ROCK1 is thought to diminish Aβ levels by enhancing lysosomal degradation of APP (Henderson et al, 2016). …”

Rho‐associated protein kinases as therapeutic targets for both vascular and parenchymal pathologies in Alzheimer's disease

“…; Henderson et al . ). Additionally, in both rodent models and AD patients, both isoforms are elevated in the brain (Herskowitz et al .…”

Glucocorticoid receptors signaling impairment potentiates amyloid‐β oligomers‐induced pathology in an acute model of Alzheimer’s disease

“…We showed that the oAβ [25][26][27][28][29][30][31][32][33][34][35] injection-induced inhibition of sAPPα and ADAM10 is associated with an activation of ROCK/PDK1 pathways. 68,75,76 ROCK activity seems to be directly upregulated by GC, 72,73,77 and ROCK/PDK1 activation after oAβ [25][26][27][28][29][30][31][32][33][34][35] is reversed by treatment with CORT113176, again constituting a vicious cycle based on feed-forward effects on GR signaling (Figure 7). 68,75,76 ROCK activity seems to be directly upregulated by GC, 72,73,77 and ROCK/PDK1 activation after oAβ [25][26][27][28][29][30][31][32][33][34][35] is reversed by treatment with CORT113176, again constituting a vicious cycle based on feed-forward effects on GR signaling …”