Targeting of RhoA-ROCK pathway activators and linked molecular signaling in Alzheimer's disease: The paving dawn for future therapy.

Rho-associated protein kinase (ROCK) is a serine/threonine kinase that plays a central role in regulating cellular processes, including growth, proliferation, survival, and migration. ROCK exists as two isoforms, ROCK1 and ROCK2, which function as the principal downstream effectors of Rho GTPases. Activation of the RhoA-ROCK signaling pathway is induced by a variety of extracellular stimuli, including angiotensin II (Ang II), platelet-derived growth factor (PDGF), integrins, and vascular endothelial growth factor (VEGF). RhoA-ROCK pathway promotes the production of amyloid beta (Aβ) and increases the formation of neurofibrillary tangles (NFTs) the hallmarks of Alzheimer's disease (AD). It has been shown that Rho-kinase inhibitors are effective against AD neuropathology and other neurodegenerative diseases through modulation of synaptic activity and neuroinflammation. To date, no clinical trials have directly evaluated the efficacy and safety of ROCK inhibitors in patients with AD. This gap highlights the need to explore alternative therapeutic strategies within the RhoA-ROCK signaling axis. In particular, targeting upstream activators of this pathway such as angiotensin II (Ang II), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), and integrin may represent a more conceivable approach to attenuate AD-related neuropathology. Modulation of these signaling inputs has the potential to suppress the aberrant RhoA-ROCK activation and its downstream pathological consequences. Accordingly, this review aims to elucidate the mechanistic role of the RhoA-ROCK pathway in AD, and to critically examine the therapeutic potential targeting its upstream activators as a therapeutic strategy for AD.