ROCK inhibitor Ripasudil reduces Alzheimer pathological proteins and enhances cellular bioenergetics

Rho-associated kinase (ROCK) inhibitors have been explored as an Alzheimer Disease (AD) therapeutic agent. In this study, we aim to determine the efficacy of a potent ROCK inhibitor, ripasudil, in impacting AD pathological protein tau in mice. The time-course study showed that ripasudil rapidly penetrated mouse brains, reaching maximal concentration half an hour post-injection. To determine the efficacy of ripasudil, we injected AppNL-G-F knock-in mice with ripasudil at 30 mg/kg and sacrificed them after three hours. We used Tandem Mass Tag labels and compared the proteomic profiles of mouse brains exposed to ripasudil to those exposed to saline. We also treated AD-patient-derived Neural Stem Cells (NSCs) with ripasudil and performed a Seahorse Mito Stress Test to evaluate their impact on mitochondrial activity. Bioinformatics analysis of the proteomic profiles revealed differentially enriched components of chromosome. The Mito Stress Test of NSCs revealed significant increases in basal oxygen consumption, ATP-linked respiration, maximal respiration, and reserve capacity oxygen consumption compared to untreated NSCs. Importantly, we found a significant reduction of Tau and pTau 396 in brains of mice treated with ripasudil. Overall, our findings highlight the feasibility and promise of ROCK inhibitor ripasudil as an AD therapeutic agent.