Clemastine fumarate attenuates tauopathy and meliorates cognition in hTau mice via autophagy enhancement

[Display omitted] •Clemastine fumarate promotes autophagy process and facilitates Tau degradation.•Clemastine fumarate makes protective effect on HEK293 cells.•Clemastine fumarate reduces glia activation and protects synapses in hTau mice.•Clemastine fumarate improves cognition functions of hTau mice. Clemastine fumarate, which has been identified as a promising agent for remyelination and autophagy enhancement, has been shown to mitigate Aβ deposition and improve cognitive function in the APP/PS1 mouse model of Alzheimer's disease. Based on these findings, we investigated the effect of clemastine fumarate in hTau mice, a different Alzheimer's disease model characterized by overexpression of human Tau protein. Surprisingly, clemastine fumarate was effective in reducing pathological deposition of Tau protein, protecting neurons and synapses from damage, inhibiting neuroinflammation, and improving cognitive impairment in hTau mice. Interestingly, chloroquine, an autophagy inhibitor, had a significant impact on total and Sarkosyl fractions of autophagy, demonstrating that it can interrupt autophagy. Notably, after administration of chloroquine, levels of Tau protein were significantly increased. When clemastine fumarate was co-administered with chloroquine, the protective effects were reversed, indicating that clemastine fumarate indeed triggered autophagy and promoted the degradation of Tau protein, while also inhibiting further Tauopathy-related neuroinflammation and synapse loss to improve cognitive function in hTau mice.