Alzheimer’s disease is characterized by the accumulation of amyloid-β plaques, aggregation of hyperphosphorylated tau (pTau), and microglia activation. Galectin-3 (Gal3) is a β-galactoside–binding protein that has been implicated in amyloid pathology. Its role in tauopathy remains enigmatic. Here, we showed that Gal3 was upregulated in the microglia of humans and mice with tauopathy. pTau triggered the release of Gal3 from human induced pluripotent stem cell–derived microglia in both its free and extracellular vesicular–associated (EV-associated) forms. Both forms of Gal3 increased the accumulation of pathogenic tau in recipient cells. Binding of Gal3 to pTau greatly enhanced tau fibrillation. Besides Gal3, pTau was sorted into EVs for transmission. Moreover, pTau markedly enhanced the number of EVs released by iMGL in a Gal3-dependent manner, suggesting a role of Gal3 in biogenesis of EVs. Single-cell RNA-Seq analysis of the hippocampus of a mouse model of tauopathy (THY-Tau22) revealed a group of pathogenic tau-evoked, Gal3-associated microglia with altered cellular machineries implicated in neurodegeneration, including enhanced immune and inflammatory responses. Genetic removal of Gal3 in THY-Tau22 mice suppressed microglia activation, reduced the level of pTau and synaptic loss in neurons, and rescued memory impairment. Collectively, Gal3 is a potential therapeutic target for tauopathy.

中文翻译：

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Galectin-3 加剧 tau 蛋白病中的小胶质细胞激活和 tau 蛋白传递

阿尔茨海默氏病的特征是β-淀粉样蛋白斑块的积累、过度磷酸化 tau (pTau) 的聚集以及小胶质细胞的激活。Galectin-3 (Gal3) 是一种 β-半乳糖苷结合蛋白，与淀粉样蛋白病理学有关。它在 tau 蛋白病变中的作用仍然是个谜。在这里，我们发现 Gal3 在患有 tau 蛋白病的人类和小鼠的小胶质细胞中表达上调。pTau 触发人诱导多能干细胞衍生的小胶质细胞释放 Gal3，无论是游离形式还是细胞外囊泡相关（EV 相关）形式。两种形式的 Gal3 都会增加受体细胞中致病性 tau 蛋白的积累。Gal3 与 pTau 的结合大大增强了 tau 纤维颤动。除了 Gal3 之外，pTau 也被分类到 EV 中进行传输。此外，pTau 以 Gal3 依赖性方式显着增加 iMGL 释放的 EV 数量，表明 Gal3 在 EV 生物发生中的作用。对 tau 蛋白病小鼠模型 (THY-Tau22) 的海马进行单细胞 RNA-Seq 分析，揭示了一组由 tau 蛋白诱发的致病性 Gal3 相关小胶质细胞，其细胞机制发生了改变，这些细胞机制与神经变性有关，包括增强的免疫和炎症反应。THY-Tau22 小鼠中 Gal3 的基因去除抑制了小胶质细胞的激活，降低了神经元中 pTau 的水平和突触损失，并挽救了记忆障碍。总的来说，Gal3 是 tau 蛋白病的潜在治疗靶点。