RhoA/ROCK/GSK3β Signaling: A Keystone in Understanding Alzheimer's Disease

Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive cognitive decline and loss of neuronal integrity. Emerging evidence suggests that RhoA, Rho-associated coiled-coil kinase (ROCK), and their downstream effector molecule glycogen synthase 3β (GSK3β) interact within a complex signaling pathway (RhoA/ROCK/GSK3β) that plays a crucial role in the pathogenesis of AD. RhoA, a small GTPase, along with its downstream effector, ROCK, regulates various cellular processes, including actin cytoskeleton dynamics, apoptosis, and synaptic plasticity. GSK3β, a serine/threonine kinase, plays a key role in neuronal function and AD pathology, including the regulation of tau phosphorylation and amyloid-beta cleavage. Overactive GSK3β has been closely linked to tau hyperphosphorylation, neurodegeneration, and the progression of AD. Thus, GSK3β has been considered as a promising therapeutic target for treating AD and mitigating cognitive impairment. However, clinical trials of GSK3β in AD have faced considerable challenges due to the complexity of the specific neuronal inhibition of GSK3β. In this review, we summarize the literature regarding the relationship of RhoA/ROCK and GSK3β signaling pathways in AD pathogenesis. We further discuss recent findings of the sTREM2-transgelin-2 (TG2) axis as a potential mediator of this complex pathway and provide our review on a novel targeting strategy for AD.