Rho-associated coiled-coil kinase 1 activation mediates amyloid precursor protein site-specific Ser655 phosphorylation and triggers amyloid pathology.

Yong‐Bo Hu,Hai‐Lun Cui,Yue Huang,Wen‐Ying Qiu,Hong‐Zhuan Chen,Ru‐Jing Ren,Gang Wang,Yong‐Fang Zhang,Chao Ma,Hao Wang,Pei‐Jing Cui

doi:10.1111/acel.13001

Abstract

Rho‐associated coiled‐coil kinase 1 (ROCK1) is proposed to be implicated in Aβ suppression; however, the role for ROCK1 in amyloidogenic metabolism of amyloid precursor protein (APP) to produce Aβ was unknown. In the present study, we showed that ROCK1 kinase activity and its APP binding were enhanced in AD brain, resulting in increased β‐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.

Highlights

Alzheimer's disease (AD) is the most prevalent form of dementia characterized by progressive cognitive decline (Goedert & Spillantini, 2006)
We further demonstrated that Rho‐associated coiled‐coil kinase 1 (ROCK1)‐ mediated amyloid precursor protein (APP) phosphorylation at S655 promotes amyloidogenic processing of APP by increasing interaction of beta‐secretase 1 (BACE1) with APP
ROCK1‐induced APP S655 phosphorylation in AD significantly promotes amyloidogenic APP processing and subse‐ quently leads to cognition deficits during the progression of AD

Summary

| INTRODUCTION

Alzheimer's disease (AD) is the most prevalent form of dementia characterized by progressive cognitive decline (Goedert & Spillantini, 2006). The disease is characterized by β‐amyloid (Aβ) deposition, neurofibrillary tangles (NFTs), and neuron loss. Among those patho‐ logical changes, the extracellular accumulation of amyloid plaques in brain derived from amyloid precursor protein (APP) cleavage is considered to be a specific hallmark of AD. The APP‐CTF domain may be involved in intracellular signaling transduction and regulation of ion channels and Ca2+ con‐ centration (Lacampagne et al, 2017). The present study aims to investigate the ROCK1 ac‐ tivity and its interaction with APP in AD mouse model and patients, identify whether APP is a phosphorylation substrate of ROCK1, and confirm the subsequent effects of ROCK1‐induced APP phosphory‐ lation on APP processing. We validate whether altering APP phosphorylation or ROCK inhibition could be a therapeutic option for AD

| METHODS AND MATERIALS

Findings

| DISCUSSION