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Cited by 76Alzheimer's disease research and treatmentsProtein Kinase Regulation and GTPase SignalingAldose Reductase and Taurine

Rho-kinase ROCK inhibitors reduce oligomeric tau protein

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Hamano, Tadanori, Shirafuji, Norimichi, Yen, Shu-Hui, Yoshida, Hirotaka, Kanaan, Nicholas M., Hayashi, Kouji, Ikawa, Masamichi, Yamamura, Osamu +3 more·2020·Neurobiology of Aging
DOI 10.1016/j.neurobiolaging.2019.12.009PMC PMC7183001
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Abstract

Neurofibrillary tangles, one of the pathological hallmarks of Alzheimer's disease, consist of highly phosphorylated tau proteins. Tau protein binds to microtubules and is best known for its role in regulating microtubule dynamics. However, if tau protein is phosphorylated by activated major tau kinases, including glycogen synthase kinase 3β or cyclin-dependent kinase 5, or inactivated tau phosphatase, including protein phosphatase 2A, its affinity for microtubules is reduced, and the free tau is believed to aggregate, thereby forming neurofibrillary tangles. We previously reported that pitavastatin decreases the total and phosphorylated tau protein using a cellular model of tauopathy. The reduction of tau was considered to be due to Rho-associated coiled-coil protein kinase (ROCK) inhibition by pitavastatin. ROCK plays important roles to organize the actin cytoskeleton, an expected therapeutic target of human disorders. Several ROCK inhibitors are clinically applied to prevent vasospasm postsubarachnoid hemorrhage (fasudil) and for the treatment of glaucoma (ripasudil). We have examined the effects of ROCK inhibitors (H1152, Y-27632, and fasudil [HA-1077]) on tau protein phosphorylation in detail. A human neuroblastoma cell line (M1C cells) that expresses wild-type tau protein (4R0N) by tetracycline-off (TetOff) induction, primary cultured mouse neurons, and a mouse model of tauopathy (rTG4510 line) were used. The levels of phosphorylated tau and caspase-cleaved tau were reduced by the ROCK inhibitors. Oligomeric tau levels were also reduced by ROCK inhibitors. After ROCK inhibitor treatment, glycogen synthase kinase 3β, cyclin-dependent kinase 5, and caspase were inactivated, protein phosphatase 2A was activated, and the levels of IFN-γ were reduced. ROCK inhibitors activated autophagy and proteasome pathways, which are considered important for the degradation of tau protein. Collectively, these results suggest that ROCK inhibitors represent a viable therapeutic route to reduce the pathogenic forms of tau protein in tauopathies, including Alzheimer's disease.

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  • Inhibition of ROCK or direct downregulation of ROCK expression results in activation of both autophagy and the UPS, indicating that RhoA/ROCK signaling negatively regulates degradation pathways.

    “Several studies have shown that inhibition of ROCK or direct downregulation of ROCK expression results in the activation of both autophagy and the UPS, indicating that RhoA/ROCK signaling negatively regulates the degradation pathways [142,143,144,145,146].”

    From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [146]

    The Results section, “ROCK inhibitors upregulated autophagy and activated proteasome,” reports that ROCK inhibitor treatment increased autophagy markers and 20S and 26S proteasome activity. The Discussion reports increased autophagic flux after ROCK knockdown, but does not report UPS activation after direct downregulation of ROCK expression. Page numbers are unavailable in our copy. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • ROCK inhibition mitigates tau pathology both in vitro and in vivo by reducing total tau levels, tau phosphorylation, and oligomerization as well as facilitating tau degradation through autophagy and proteasome pathways.

    “Tau is a substrate for phosphorylation by ROCK [181], and ROCK inhibition was found to mitigate tau pathology both in vitro and in vivo by reducing total tau levels, tau phosphorylation, and oligomerization as well as facilitating tau degradation through autophagy and proteasome pathways [146,190].”

    From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [146]

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Authors
Hamano, T., Shirafuji, N., Yen, S.-H., Yoshida, H., Kanaan, N. M., Hayashi, K., Ikawa, M., Yamamura, O., Fujita, Y., Kuriyama, M., & Nakamoto, Y.
Affiliations
  • University of Fukui (JP)
  • Mayo Clinic in Florida (US)
  • National Center for Geriatrics and Gerontology (JP)
  • Michigan State University (US)
  • Fuji Heavy Industries Health Insurance Society Ota Memorial Hospital (JP)
Corresponding author
Hamano, Tadanori
ORCID
Venue
Neurobiology of Aging
Publisher
Elsevier BV
Published
2020-05
Volume
89
Pages
41-54
ISSN
0197-4580 (ISSN-L)
DOI
10.1016/j.neurobiolaging.2019.12.009
PMC
PMC7183001
OpenAlex
W2995446691
Cited by
76
References
4
Citations by year
2026: 7 · 2025: 13 · 2024: 15 · 2023: 8 · 2022: 18 · 2021: 10 · 2020: 5
FWCI
5.53
Type
journal article
Language
en
Open access
Licence
Locations
  • Neurobiology of Aging (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • University of Fukui
  • National Center for Gerontology and Gerontology
  • Japan Foundation for Aging and Health
  • NIH (R01NS082730, R01AG044372)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Aldose Reductase and Taurine
Keywords
ROCK inhibitor, rocks, tau protein, tau phosphorylation, neurofibrillary tangles, Alzheimer's disease, tauopathy, fasudil, Y-27632, glycogen synthase kinase-3β, cyclin-dependent kinase 5, protein phosphatase 2A, caspase cleavage, autophagy, proteasome, interferon-gamma, actin cytoskeleton
MeSH terms
Alzheimer Disease, Animals, Autophagy, Cells, Cultured, Disease Models, Animal, Enzyme Inhibitors, Humans, Phosphorylation, Quinolines, Signal Transduction, Neurofibrillary Tangles, tau Proteins, Tauopathies, Cell Line, Tumor, Proteasome Endopeptidase Complex, Mice, rho-Associated Kinases, Proteolysis

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