Galectin-9 activates the TLR4-NLRP3 inflammasome pathway and promotes tau pathology in Alzheimer’s disease

Tau deposition, microglial activation, and neuroinflammation are prominent features of Alzheimer's disease (AD). Galectin-9 (Gal-9), one of the most abundant beta-galactosidase-binding proteins secreted by active microglia, is elevated in brain tissue and cerebrospinal fluid in patients with AD, associating with cognitive impairments. However, whether Gal-9 is involved in the onset of AD pathology remains unclear. Here, we report that the expression and secretion of Gal-9 are increased in microglia exposed to tau fibrils and in the brain tissue of tau P301S transgenic mice. Gal-9 binds to toll-like receptor 4 (TLR4) on microglia and activates the NLR family, pyrin domain containing 3 (NLRP3) inflammasome, promoting the secretion of interleukin-1β (IL-1β) and IL-18, which are toxic to neurons. Genetic ablation of Gal-9 in tau P301S mice diminishes microglial activation and tau deposition, preserves synaptic integrity, and improves cognitive function. Furthermore, Gal-9 knockout also halted the spread of tau pathology induced by the intracerebral injection of tau fibrils, whereas the intracerebral injection of Gal-9 promoted tau pathology. Overall, our findings demonstrate that microglial activation facilitates tau pathology through Gal-9 and support the therapeutic potential of targeting the Gal-9-TLR4-NLRP3 axis to treat AD.