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Cited by 33Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchProtein Kinase Regulation and GTPase Signaling

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

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Hu, Yong‐Bo, Ren, Ru‐Jing, Zhang, Yong‐Fang, Huang, Yue, Cui, Hai‐Lun, Ma, Chao, Qiu, Wen‐Ying, Wang, Hao +3 more·2019·Aging Cell
DOI 10.1111/acel.13001PMC PMC6718535
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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.

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  • ROCK directly interacts with APP and phosphorylates its Ser655 residue, promoting amyloidogenic processing of APP by increasing the interaction of BACE1 with APP.

    “It was recently reported that ROCK directly interacts with APP and phosphorylates its Ser655 residue, promoting amyloidogenic processing of APP by increasing the interaction of β-site APP cleaving enzyme 1 (BACE1) with APP [194].”

    From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [194]

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Cited by

Sorted by citations

Authors
Hu, Y., Ren, R., Zhang, Y., Huang, Y., Cui, H., Ma, C., Qiu, W., Wang, H., Cui, P., Chen, H., & Wang, G.
Affiliations
  • Shanghai Jiao Tong University (CN)
  • Capital Medical University (CN)
  • Department of Neurology Neuroscience Institute Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine Shanghai China
  • Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
  • Department of Human Anatomy, Histology and Embryology, Institute of Basic Medical Sciences, Neuroscience Center, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College Beijing China
Corresponding author
  • Chen, Hong‐Zhuan
  • Wang, Gang
ORCID
Venue
Aging Cell
Publisher
Wiley
Published
2019-07-09
Volume
18
Issue
5
Pages
e13001-e13001
ISSN
  • 1474-9718 (ISSN-L)
  • 1474-9726
DOI
10.1111/acel.13001
PMC
PMC6718535
OpenAlex
W2961532768
Cited by
33
References
1
Citations by year
2026: 7 · 2025: 6 · 2024: 7 · 2023: 3 · 2022: 2 · 2021: 7 · 2019: 1
FWCI
1.68
Type
journal article
Language
en
Open access
Licence
Locations
  • Aging Cell (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • National Natural Science Foundation of China (81171027, 81200842, 81573401, 81671043, 81501086)
  • Shanghai Education Development Foundation
  • Chinese Academy of Medical Sciences
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords
ROCK1, amyloid precursor protein, amyloid-beta, Alzheimer's disease, APP/PS1 mice, Y-27632, learning and memory, amyloid pathology
MeSH terms
Alzheimer Disease, Amides, Animals, Cells, Cultured, Humans, Mice, Inbred C57BL, Mice, Transgenic, Phosphorylation, Phosphoserine, Pyridines, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, RNA, Small Interfering, Protein Kinase Inhibitors, Mice, rho-Associated Kinases, HEK293 Cells

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