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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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 5

Loss of Gal3 rescues tauopathy in THY-Tau22 mice.

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Loss of Gal3 rescues tauopathy in THY-Tau22 mice. (A) Schematic diagram ...
(A) Schematic diagram illustrating the study design to identify the roles of Gal3 in Tau22 mice. IHC staining and quantification for (B and C) MC1 and (D and E) AT100 in mouse hippocampi, MC1: n = 8 for Tau22/Lgals3+/+, n = 7 for Tau22/Lgals3–/–; AT100: n = 5 mice. Each dot represents the average value of each animal. (F) Immunoblot analysis of sarkosyl soluble mouse hippocampi (11 months) stained for MC1, AT100, Tau5, demethylated PP2A subunit C (inactive PP2Ac), PP2Ac, pGSK-3β Y216, GSK-3β, pCaMKII-α, and CaMKII-α. (G) Quantification of the data in F, n = 7 mice. (H) Quantification of the time to platform in the 5-day training section of the Morris water maze, n = 13 for WT, n = 17 for Lgals3–/–, n = 12 for Tau22/Lgals3+/+, n = 16 for Tau22/Lgals3–/–. (I), Quantification of the time spent in quadrant 4 (Q4, the quadrant with the hidden platform during the training section) versus all other quadrants (a.o., average of 3 other quadrants) on probe trial Day 8. Data are shown as the mean ± SEM. (J and K) IHC staining and quantification of CD68 in Tau22/Lgals3–/– and Tau22/Lgals3+/+ mice, n = 5 mice, 3 fields per animal. (L) IHC staining of Homer 1 and VGLUT1 in the CA1 region of Tau22/Lgals3–/– and control mice. (M) Quantification of the staining in L, n = 8 mice, 3 fields per animal. Scale bars: 500 μm (B and D), 10 μm (J), 2 μm (L). Data in H and M were analyzed by 2-way ANOVA with Tukey’s test. Other data were analyzed with a 2-tailed unpaired t test, and all violin plots show the median with the 25th and 75th percentiles. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.