Galectin-3 aggravates microglial activation and tau transmission in tauopathy
Alzheimer's disease is characterized by the accumulation of amyloid-beta plaques, aggregation of hyperphosphorylated tau, and microglia activation. Galectin-3 is a beta galactoside-binding protein that has been implicated in amyloid pathology. Its role in tauopathy remains enigmatic. Here, we showed that galectin-3 was upregulated in the microglia of humans and mice with tauopathy. Hyperphosphorylated tau triggered the release of galectin-3 from human induced pluripotent stem cell-derived microglia in both its free and extracellular vesicular-associated forms. Both forms of galectin-3 increased the accumulation of pathogenic tau in recipient cells. Binding of galectin-3 to hyperphosphorylated tau greatly enhanced tau fibrillation. Besides galectin-3, hyperphosphorylated tau was sorted into extracellular vesicles for transmission. Moreover, hyperphosphorylated tau markedly enhanced the numbers of extracellular vesicles released by human induced pluripotent stem cell-derived microglia in a galectin-3-dependent manner, suggesting a role of galectin-3 in extracellular vesicles biogenesis. Single-cell RNA-seq analysis of the hippocampus of a mouse model of tauopathy revealed a group of pathogenic tau-evoked, galectin-3-associated microglia with altered cellular machineries, including enhanced immune and inflammatory responses. Genetic removal of galectin-3 in mouse model of tauopathy suppressed microglia activation, reduced the level of hyperphosphorylated tau and synaptic loss in neurons, and rescued the memory impairment. Collectively, galectin-3 is a potential therapeutic target for tauopathy.