Role of RhoA/ROCK signaling in Alzheimer’s disease

Cai, Ruo-Lan; Wang, Yangyang; Huang, Zhicheng; Zou, Qian; Pu, Yinshuang; Yu, Chunhao; Cai, Zhiyou

doi:10.1016/j.bbr.2021.113481

Cited by 55 publications

(29 citation statements)

References 102 publications

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“…Rho kinase (ROCK), a serine/threonine kinase, is a downstream effector of member A of the Ras homologous gene family (RhoA) and is involved in regulating cell migration, proliferation and survival ( Cai et al, 2021 ). The abnormal activation of RhoA/ROCK signaling is involved in the early response to abnormal mechanical stimulation, which is considered to be a promoter of the progression of OA.…”

Section: Adipokine Signaling Pathways In Osteoarthritismentioning

confidence: 99%

“…Calcium Calmodulin-Dependent Kinase II (CaMKII) is a serine/threonine protein kinase and a general integrator of Ca 2+ signaling ( Wei et al, 2018 ). The upregulation of CaMKII is highly correlated with the pathogenesis and progression of OA and the reactivation of articular cartilage hypertrophy ( Saitta et al, 2019 ; Cai et al, 2021 ). Studies have demonstrated that activated phosphorylated-CaMKII may play a key role in chondrocyte apoptosis through the MAPK and Akt/mTOR signaling pathways ( Wei et al, 2018 ).…”

Section: Adipokine Signaling Pathways In Osteoarthritismentioning

confidence: 99%

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Adipokine Signaling Pathways in Osteoarthritis

Zhang

Lin

Yan

et al. 2022

Front. Bioeng. Biotechnol.

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Osteoarthritis (OA) is a debilitating joint disease that affects millions of individuals. The pathogenesis of OA has not been fully elucidated. Obesity is a well-recognized risk factor for OA. Multiple studies have demonstrated adipokines play a key role in obesity-induced OA. Increasing evidence show that various adipokines may significantly affect the development or clinical course of OA by regulating the pro/anti-inflammatory and anabolic/catabolic balance, matrix remodeling, chondrocyte apoptosis and autophagy, and subchondral bone sclerosis. Several signaling pathways are involved but still have not been systematically investigated. In this article, we review the cellular and molecular mechanisms of adipokines in OA, and highlight the possible signaling pathways. The review suggested adipokines play important roles in obesity-induced OA, and exert downstream function via the activation of various signaling pathways. In addition, some pharmaceuticals targeting these pathways have been applied into ongoing clinical trials and showed encouraging results. However, these signaling pathways are complex and converge into a common network with each other. In the future work, more research is warranted to further investigate how this network works. Moreover, more high quality randomised controlled trials are needed in order to investigate the therapeutic effects of pharmaceuticals against these pathways for the treatment of OA. This review may help researchers to better understand the pathogenesis of OA, so as to provide new insight for future clinical practices and translational research.

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Section: Adipokine Signaling Pathways In Osteoarthritismentioning

confidence: 99%

Section: Adipokine Signaling Pathways In Osteoarthritismentioning

confidence: 99%

Adipokine Signaling Pathways in Osteoarthritis

Zhang

Lin

Yan

et al. 2022

Front. Bioeng. Biotechnol.

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“…ROCK inhibitors could also reduce synaptic damage and promote nerve regeneration in AD mice (Yan et al, 2021 ). Recent studies indicated that ROCK2 is a promising therapeutic target for AD (Cai et al, 2021 ; Weber & Herskowitz, 2021 ). Some studies indicated that acrolein is closely related to ROCK1 (Fukutsu et al, 2021 ) but no relevant biological experiment conducted to substantiate the relationship between acrolein‐induced early AD and ROCK2 in the brain.…”

Section: Discussionmentioning

confidence: 99%

“…ROCK is a serine/threonine kinase and two isoforms, ROCK 1 and ROCK 2, were isolated till now (Cai et al, 2021). ROCK1 is control group, ### p < 0.001 vs. model group mainly distributed in peripheral tissues such as the heart and skeletal muscle, and ROCK2 is mainly distributed in the nervous system (Yan et al, 2019).…”

Section: Discussionsmentioning

confidence: 99%

Acrolein, an endogenous aldehyde induces synaptic dysfunction in vitro and in vivo: Involvement of RhoA/ROCK2 pathway

Zhu

Wang

et al. 2022

Aging Cell

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Acrolein, an unsaturated aldehyde, is increased in the brain of Alzheimer's disease (AD) patients and identified as a potential inducer of sporadic AD. Synaptic dysfunction, as a typical pathological change occurring in the early stage of AD, is most closely associated with the severity of dementia. However, there remains a lack of clarity on the mechanisms of acrolein inducing AD‐like pathology and synaptic impairment. In this study, acrolein‐treated primary cultured neurons and mice were applied to investigate the effects of acrolein on cognitive impairment and synaptic dysfunction and their signaling mechanisms. In vitro, ROCK inhibitors, Fasudil, and Y27632, could attenuate the axon ruptures and synaptic impairment caused by acrolein. Meanwhile, RNA‐seq distinct differentially expressed genes in acrolein models and initially linked activated RhoA/Rho‐kinase2 (ROCK2) to acrolein‐induced synaptic dysfunction, which could regulate neuronal cytoskeleton and neurite. The Morris water maze test and in vivo field excitatory postsynaptic potential (fEPSP) were performed to evaluate spatial memory and long‐term potential (LTP), respectively. Acrolein induced cognitive impairment and attenuated LTP. Furthermore, the protein level of Synapsin 1 and postsynaptic density 95 (PSD95) and dendritic spines density were also decreased in acrolein‐exposed mice. These changes were improved by ROCK2 inhibitor Fasudil or in ROCK2 +/− mice. Together, our findings suggest that RhoA/ROCK2 signaling pathway plays a critical role in acrolein‐induced synaptic damage and cognitive dysfunction, suggesting inhibition of ROCK2 should benefit to the early AD.

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“…We recently described that Rock2 accumulation and activation in neurons triggers dendrite disruption and synapse loss, leading to memory impairment ( Bobo-Jimenez et al, 2017 ). Moreover, Rock2 expression resulted in lower dendritic spine density ( Henderson et al, 2019 ), whereas Rock inhibition increases the number of thin spines and filopodia, which would enhance synapse formation and neuronal plasticity ( Swanger et al, 2015 ; Cai et al, 2021 ). Interestingly, dendritic dystrophy ( Cochran et al, 2014 ; Shi et al, 2020 ) and synapse loss ( Terry et al, 1991 ; Scheff et al, 2007 ) have both been detected in early-stage AD brains and are correlated with cognitive decline.…”

Section: Introductionmentioning

confidence: 99%

Amyloid-β Induces Cdh1-Mediated Rock2 Stabilization Causing Neurodegeneration

et al. 2022

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Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline, which is causally related to the accumulation of abnormally folded amyloid-β (Aβ) peptide and hyperphosphorylated tau protein aggregates. The dendritic spine regulator Rho protein kinase 2 (Rock2) accumulates in the brain at the earliest stages of AD and remains increased during disease progression. However, the molecular mechanism that upregulates Rock2 in AD, and its role in the disease progression, are unknown. Here, we found that oligomers of the amyloidogenic fragment 25–35 of the Aβ peptide (Aβ25-35) trigger Rock2 accumulation and activation in mouse cortical neurons in primary culture and in mouse hippocampus in vivo. Neuronal apoptotic death and memory impairment caused by Aβ25-35 administration were rescued by genetic and pharmacological inhibition of Rock2 activity. Mechanistically, Aβ25-35 elicited cyclin dependent kinase-5 (Cdk5)-mediated phosphorylation of Cdh1, a cofactor that is essential for the activity of the E3 ubiquitin ligase anaphase-promoting complex/cyclosome (APC/C) in neurons. Notably, phosphorylated Cdh1 was disassembled from the APC/C complex, causing its inactivation and subsequent Rock2 protein stabilization and activation. Moreover, Aβ25-35-induced neuronal apoptosis was prevented by expressing a phosphodefective form of Cdh1, but not by a phosphomimetic Cdh1. Finally, Cdh1 inactivation, using both genetic and pharmacological approaches, enhanced Aβ25-35-mediated neuronal death through a mechanism that was prevented by inhibition of Rock2 activity. These results indicate that the Cdk5-Cdh1 signaling pathway accounts for the increased Rock2 activity by amyloidogenic Aβ peptides and that this mechanism may contribute to neurodegeneration and memory loss in AD.

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Role of RhoA/ROCK signaling in Alzheimer’s disease

Cited by 55 publications

References 102 publications

Adipokine Signaling Pathways in Osteoarthritis

Adipokine Signaling Pathways in Osteoarthritis

Acrolein, an endogenous aldehyde induces synaptic dysfunction in vitro and in vivo: Involvement of RhoA/ROCK2 pathway

Amyloid-β Induces Cdh1-Mediated Rock2 Stabilization Causing Neurodegeneration

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