P4–424: Targeting kinases hyperphosphorylating tau protein: Elucidation of kinase inhibition profile most efficient in restoring physiological tau phosphorylation

Tauopathy, next to beta amyloidosis, constitutes the second hallmark of Alzheimer's Disease. Hyperphosphorylation of tau is considered responsible for aggregation into oligomers and eventually neurofibrillary tangles. Direct inhibition of protein kinases implicated in AD related tau hyperphosphorylation constitutes one of the strategies for disease modifying treatment of AD and other tauopathies. While several different kinases are involved in pathological tau hyperphosphorylation none of them is sufficient alone to induce tauopathy in animal models. We aimed at elucidation of the kinase inhibition profile (tau kinases: DYRK1A, CDK5, GSK3b and MARK1) that would most efficiently restore physiological tau phosphorylation levels at disease relevant epitopes. Compounds from SELVITA proprietary library of kinase inhibitors and reference compounds showing different inhibition profiles of four tau kinases, from selective to pan-tau-kinase inhibitors were tested in SH-SY5Y neuroblastoma cell line model with tau hyperphosphorylation induced by okadaic acid. Brain penetrant inhibitors were also examined in vivo acute LPS challenge model (wild type mice). Western blot analysis of cell lysates and isolated hippocampal homogenates was conducted to monitor tau phosphorylation in AD relevant epitopes. Comparison of different kinase inhibition profiles shows that most efficient decrease in pathological hyperphosphorylation levels results from pan-tau inhibition profile. These results constitute a guideline for molecular target profile of kinase inhibitors targeting tauopaties currently discovered in SELVITA.