Galectin-3 aggravates microglial activation and tau transmission in tauopathy

Jian Jing Siew, Hui Mei Chen, Feng Lan Chiu, Chia Wei Lee, Yao Ming Chang, Hung Lin Chen, Thi Ngoc Anh Nguyen, Hung Ting Liao, Mengyu Liu, Hsiao Tien Hagar, Yung Chen Sun, Hsing Lin Lai, Min Hao Kuo, David Blum, Luc Buée, Lee Way Jin, Shih Yu Chen, Tai Ming Ko, Jie Rong Huang, Hung Chih KuoFu Tong Liu, Yijuang Chern*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

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.

Original languageEnglish
Article numbere165523
JournalJournal of Clinical Investigation
Volume134
Issue number2
DOIs
StatePublished - 16 Jan 2024

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