VER155008 rescues cognitive impairment in P301S tauopathy mice by promoting HSPA8-mediated lipophagy

Alzheimer's disease (AD) features tau accumulation and pathogenic lipid droplet (LD) buildup, driving neurodegeneration through oxidative stress and neuroinflammation. The chaperone heat shock protein family A member 8 (HSPA8) is upregulated in AD, which may have implications for impaired LD clearance via lipophagy. We investigated whether targeting HSPA8 with the small-molecule antagonist VER155008 alleviates tau pathology and cognitive deficits by activating lipophagy in P301S tauopathy models. P301S tau transgenic mice and HEK293T-P301S cells were utilized. Western blotting, immunohistochemistry, and immunofluorescence were performed to assess HSPA8 levels, lipophagy, tau proteins, and inflammatory markers. VER155008 or vehicle control was administered to P301S mice for four weeks, starting at seven months of age. Cognitive function was evaluated using the Morris water maze and novel object recognition tests. Synaptic density was assessed through Golgi staining and electron microscopy. HSPA8 was elevated in P301S mice, correlating with impaired lipophagy and suppressed AMP-activated protein kinase (AMPK) activity. VER155008 treatment restored cognitive function and synaptic density. Critically, it activated lipophagy and reduced hippocampal LDs and tau pathology. Moreover, HSPA8 overexpression suppressed lipophagy and increased both LD accumulation and tau pathology. Inhibition of HSPA8 by VER155008 activates AMPK-mediated lipophagy, concurrently reducing tau pathology, oxidative stress, and neuroinflammation in AD models. These beneficial effects were eliminated by treatment with the AMPK inhibitor Compound C. This identifies the HSPA8-lipophagy axis as a promising therapeutic target for tauopathies.