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

Aging Cell. 2019 Oct;18(5):e13001. doi: 10.1111/acel.13001. Epub 2019 Jul 9.

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.

Keywords: Alzheimer's disease; Rho-associated coiled-coil kinase 1; amyloid precursor protein; phosphorylation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / drug therapy
  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology*
  • Amides / pharmacology
  • Amyloid beta-Peptides / antagonists & inhibitors
  • Amyloid beta-Peptides / metabolism*
  • Amyloid beta-Protein Precursor / chemistry*
  • Amyloid beta-Protein Precursor / metabolism*
  • Animals
  • Cells, Cultured
  • HEK293 Cells
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Phosphorylation / drug effects
  • Phosphoserine / metabolism*
  • Protein Kinase Inhibitors / pharmacology
  • Pyridines / pharmacology
  • RNA, Small Interfering / pharmacology
  • rho-Associated Kinases / antagonists & inhibitors
  • rho-Associated Kinases / metabolism*

Substances

  • Amides
  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Protein Kinase Inhibitors
  • Pyridines
  • RNA, Small Interfering
  • Y 27632
  • Phosphoserine
  • ROCK1 protein, human
  • rho-Associated Kinases