ROCK Inhibitor Fasudil Attenuates Neuroinflammation and Associated Metabolic Dysregulation in the Tau Transgenic Mouse Model of Alzheimer's Disease.

ABSTRACT

The pathological manifestations of Alzheimer's disease (AD) include not only brain amyloid ß protein (Aß) containing neuritic plaques and hyperphosphorylated tau (p-tau) containing neurofibrillary tangles but also microgliosis, astrocytosis, and neurodegeneration mediated by metabolic dysregulation and neuroinflammation. METHOD: While antibody-based therapies targeting Aß have shown clinical promise, effective therapies targeting metabolism, neuroinflammation, and p-tau are still an urgent need. Based on the observation that Ras homolog (Rho)-associated kinases (ROCK) activities are elevated in AD, ROCK inhibitors have been explored as therapies in AD models. This study determines the effects of fasudil, a ROCK inhibitor, on neuroinflammation and metabolic regulation in the P301S tau transgenic mouse line PS19 that models neurodegenerative tauopathy and AD. Using daily intraperitoneal (i.p.) delivery of fasudil in PS19 mice, we observed a significant hippocampal-specific decrease of the levels of phosphorylated tau (pTau Ser202/Thr205), a decrease of GFAP+ cells and glycolytic enzyme Pkm1 in broad regions of the brain, and a decrease in mitochondrial complex IV subunit I in the striatum and thalamic regions. RESULTS: Although no overt detrimental phenotype was observed, mice dosed with 100 mg/kg/day for 2 weeks exhibited significantly decreased mitochondrial outer membrane and electron transport chain (ETC) protein abundance, as well as ETC activities. CONCLUSION: Our results provide insights into dose-dependent neuroinflammatory and metabolic responses to fasudil and support further refinement of ROCK inhibitors for the treatment of AD.