Rho‐associated protein kinase 1 (ROCK 1) is increased in Alzheimer's disease and ROCK 1 depletion reduces amyloid‐β levels in brain
Open accessAbstract
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 (ROCK 1 and ROCK 2) is proposed to curb Aβ levels, and mechanisms that underlie ROCK 2′s effects on Aβ production are defined. How ROCK 1 affects Aβ generation remains a critical barrier. Here, we report that ROCK 1 protein levels were elevated in mild cognitive impairment due to AD (MCI) and AD brains compared to controls. Aβ42 oligomers marginally increased ROCK 1 and ROCK 2 protein levels in neurons but strongly induced phosphorylation of Lim kinase 1 (LIMK 1), suggesting that Aβ42 activates ROCK s. RNA i depletion of ROCK 1 or ROCK 2 suppressed endogenous Aβ40 production in neurons, and Aβ40 levels were reduced in brains of ROCK 1 heterozygous knock‐out mice compared to wild‐type littermate controls. ROCK 1 knockdown decreased amyloid precursor protein (APP), and treatment with bafilomycin accumulated APP levels in neurons depleted of ROCK 1. These observations suggest that reduction of ROCK 1 diminishes Aβ levels by enhancing APP protein degradation. Collectively, these findings support the hypothesis that both ROCK 1 and ROCK 2 are therapeutic targets to combat Aβ production in AD. imageMitigating amyloid‐β (Aβ) levels is a rational strategy for Alzheimer's disease (AD) treatment, however, therapeutic targets with clinically available drugs are lacking. We hypothesize that Aβ accumulation in mild cognitive impairment because of AD (MCI) and AD activates the RhoA/ROCK pathway which in turn fuels production of Aβ. Escalation of this cycle over the course of many years may contribute to the buildup of amyloid pathology in MCI and/or AD.
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Increased RhoA/ROCK activation promotes increased Aβ production, which in turn potentiates RhoA/ROCK activation and enhances Aβ build-up, forming a positive feedback loop.
“This is suggestive of a positive feedback loop where increased RhoA/ROCK activation promotes increased Aβ production, which in turn potentiates RhoA/ROCK activation and enhances the Aβ build-up [191].”
From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [191]
Targeting the ROCK1 isoform reduces Aβ levels in primary neuronal cultures by enhancing APP protein degradation, probably through induction of autophagy.
“It was later found that also targeting the ROCK1 isoform reduces Aβ levels in primary neuronal cultures by enhancing APP protein degradation, probably through induction of autophagy [191].”
From RhoA Signaling in Neurodegenerative Diseases (2022) · cites this paper as [191]
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Protein kinase inhibitors as therapeutics in neurodegenerative and psychiatric disorders
Tridente, G., Jana, A., Nath, A., & Ashraf, G. M. (2023) · Receptor Tyrosine Kinases in Neurodegenerative and Psychiatric Disorders · doi:10.1016/b978-0-443-18677-6.00015-4 · Cited by 8 · see citing works
- Authors
- Henderson, B. W., Gentry, E. G., Rush, T., Troncoso, J. C., Thambisetty, M., Montine, T. J., & Herskowitz, J. H.
- Affiliations
- University of Alabama at Birmingham (US)
- Johns Hopkins University (US)
- National Institute on Aging (US)
- Stanford Medicine (US)
- Corresponding author
- Herskowitz, Jeremy H.
- ORCID
- Venue
- Journal of Neurochemistry
- Publisher
- Wiley
- Published
- 2016-07
- Volume
- 138
- Issue
- 4
- Pages
- 525-531
- ISSN
- 0022-3042 (ISSN-L)
- 1471-4159
- PMC
- PMC4980252
- OpenAlex
- W2462492481
- Cited by
- 120
- References
- 3
- Citations by year
- 2026: 13 · 2025: 10 · 2024: 9 · 2023: 12 · 2022: 12 · 2021: 20 · 2020: 12 · 2019: 17 · 2018: 11 · 2017: 3 · 2016: 1
- FWCI
- 7.30
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Neurochemistry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (AG043552‐05)
- Alzheimer's Association (2015‐NIRG‐339422)
- National Institute on Aging
- 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, ROCK2, Alzheimer's disease, amyloid-beta, Aβ40, amyloid precursor protein, LIM kinase 1, RhoA/ROCK signaling, mild cognitive impairment, bafilomycin, therapeutic target
- MeSH terms
- Alzheimer Disease, Animals, Brain, Disease Models, Animal, Humans, Mice, Transgenic, Neurons, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, rho-Associated Kinases, HEK293 Cells
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