Inhibition of caspase-1 ameliorates tauopathy and rescues cognitive impairment in SAMP8 mice

The inflammasome assembles leading to increased cleavage and activity of Caspase-1 and downstream IL-1β release, which plays a significant role in the pathogenesis of Alzheimer's disease (AD). Previous studies have shown that caspase-1-mediated neuroinflammation occurs early in AD process. However, the detailed role of Caspase-1 in aging-related AD-like neuropathology is still unclear so far. In this study, by using SAMP8 mice, an animal model of accelerated aging, we detected the levels of Caspase-1 in brains of 3-, 7-, and 11-month-old mice and observed that Caspase-1 was activated during aging process. More importantly, we provided the evidence that VX-765, a selective inhibitor of Caspase-1, significantly rescued spatial learning and memory impairments and reduced tau hyperphosphorylation in brains of SAMP8 mice at early stages of the disease. This amelioration might be attributed to IL-1β-induced hypoactivation of tau kinases. Our results imply that Caspase-1 may represent as a potential therapeutic target for neurodegenerative tauopathies.