Omipalisib reduces hyperphosphorylated tau protein by modulating mTOR-autophagy pathway

Tauopathies are neurodegenerative diseases characterized by the presence of hyperphosphorylated tau (p-tau) and neurofibrillary tangles. Autophagy is a critical self-degradation mechanism that preserves cellular homeostasis and function, including the clearance of misfolded proteins. Autophagy is impaired in tauopathies, resulting in excessive accumulation of p-tau. Omipalisib, a dual phosphatidylinositol 3-kinase/mammalian target of rapamycin (PI3K/mTOR) inhibitor, was explored in a phase I clinical trial involving solid tumors and lymphoma. In this study, we aimed to investigate the effects of omipalisib on tauopathy both in vitro and in vivo. Omipalisib increased the levels of protein LC3B and decreased that of p62 in human tau (P301L)-expressing SH-SY5Y stable (SH-Tau) cells by inhibiting mTOR activation in a time-dependent manner. In our study, we hypothesized that omipalisib, a PI3K/mTOR inhibitor, could remove accumulated tau and inhibit memory decline by activating autophagy. Additionally, omipalisib reduced tau phosphorylation in SH-Tau cells without inducing cytotoxicity. Upon administration of 6-month-old PS19 mice with omipalisib (1 mg/kg) for 2 months, the levels of both RIPA-soluble and RIPA-insoluble p-tau were decreased, and spatial memory dysfunction was alleviated in omipalisib-treated PS19 mice. Overall, these results show that omipalisib decreases the expression of p-tau by modulation mTOR-autophagy pathway, resulting in the amelioration of spatial memory deficits. This study highlighted the potential of omipalisib as a candidate treatment for tauopathies.