Galectin-3 aggravates microglial activation and tau transmission in tauopathy
Jian Jing Siew, … , Fu-Tong Liu, Yijuang Chern
Jian Jing Siew, … , Fu-Tong Liu, Yijuang Chern
Published November 21, 2023
Citation Information: J Clin Invest. 2024;134(2):e165523. https://doi.org/10.1172/JCI165523.
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Research Article Neuroscience

Galectin-3 aggravates microglial activation and tau transmission in tauopathy

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.

Authors

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 Kuo, Fu-Tong Liu, Yijuang Chern

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Figure 2

Pathogenic tau triggers microglial activation via Gal3.

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Pathogenic tau triggers microglial activation via Gal3. (A) RNA-Seq anal...
(A) RNA-Seq analysis of iMGL pretreated for 24 hours with TD139 (10 μM, Gal3 inhibition) and 6 hours with pTau (50 nM) and controls. (B) Volcano plots show the DEGs identified in the pTau versus Con and pTau plus TD139 versus pTau groups. Red and blue dots indicate upregulated and downregulated DEGs, respectively, and enlarged green dots indicate Gal3-ER genes. Cutoff of significance, |Log2 FC| > 0.55 and P < 0.05 (C) Differential expression analysis of the RNA-Seq data in (B), Log2 FC in pTau versus Con (x-axis) and pTau+TD139 versus pTau (y-axis). Upregulated DEGs are shown in the right part (pTau-activated genes) or upper part (TD139-activated genes) of the graph, and downregulated DEGs are shown in the left part (pTau-inhibited genes) or lower part (TD139-inhibited genes) of the graph. Red dots and blue dots indicate upregulated and downregulated DEGs, respectively, while green dots indicate DEGs normalized by Gal3 inhibition (TD139). (D) GO enrichment analysis of DEGs upregulated under early pTau effects in iMGL identified by RNA-Seq. (E) GO enrichment analysis of downregulated DEGs identified in pTau plus TD139 versus pTau iMGL. (F and G) q-RT-PCR analysis of proinflammatory genes (IL1α, IL1β, IL6, and TNFα) in iMGL treated with pTau for 6 hours, n = 3 iMGL line, ***P < 0.001, ****P < 0.0001. (H) ELISA of conditioned medium collected from iMGL (iMCM) treated with pTau and a Gal3 inhibitor, n = 6, 3 iMGL lines from 2 independent differentiations, pTau versus Con ****P < 0.0001, and pTau+TD139 versus pTau, ####P < 0.0001. (I) Schematic diagram illustrating the effect of pTau and Gal3 inhibition on microglial activation.