Galectin-3 promotes Aβ oligomerization and Aβ toxicity in a mouse model of Alzheimer's disease
Galectin-3 promotes Aβ oligomerization and Aβ toxicity in a mouse model of Alzheimer's disease
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DOI：
10.1038/s41418-019-0348-z
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发表时间：
2020-01-01
影响因子：
12.4
通讯作者：
Lee, Eminy H. Y.
中科院分区：
文献类型：
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作者：
Tao, Chih-Chieh;Cheng, Kuang-Min;Lee, Eminy H. Y.
淀粉样蛋白-β (Aβ) 寡聚体在很大程度上启动了阿尔茨海默病 (AD) 病理学基础的级联反应。半乳糖凝集素-3 (Gal-3) 是半乳糖凝集素蛋白家族的成员，可促进炎症反应并增强癌细胞的同型聚集。在这里，我们研究了 Gal-3 在 Aβ 寡聚化和 Aβ 毒性中的作用和作用机制。使用野生型(WT)和Gal-3敲除(KO)小鼠，APP/PS1；WT小鼠，APP/PS1；Gal-3(+/-)小鼠以及来自正常受试者和AD患者的脑组织。我们发现注射Aβ的Gal-3 KO小鼠中Aβ寡聚化减少，而Gal-3的过度表达增强了注射Ac的小鼠海马中的Aβ寡聚化。 Gal-3 表达显示出年龄依赖性增加，与 APP/PS1 小鼠中的内源性 Aβ 寡聚化平行。此外，与APP/PS1；WT小鼠相比，APP/PS1；Gal-3(+/-)小鼠中Aβ寡聚化、Ibal表达、GFAP表达和淀粉样蛋白斑积累减少。与 APP/PS1;WT 小鼠相比，APP/PS1;Gal-3(+/-) 小鼠还表现出更好的采集和保留性能。在研究 Gal-3 促进 A beta 寡聚化的机制时，我们发现 Gal-3 主要与 Iba1 共定位，并且小胶质细胞分泌的 Gal-3 直接与 A beta 相互作用。 Gal-3 还与骨髓细胞 2 上表达的触发受体相互作用，然后介导 Gal-3 激活小胶质细胞以进一步表达 Gal-3 的能力。免疫组织化学分析表明，Gal-3 的分布与 APP/PS1 小鼠中内源性 Aβ 的分布重叠，并与淀粉样斑块的分布部分重叠。此外，Gal-3 KO 小鼠中 Aβ 降解酶脑啡肽酶的表达增加，这与整合素介导的信号传导增强有关。一致的是，AD 患者额叶中的 Gal-3 表达也与 Aβ 寡聚化同时增加。由于 APP/PS 1 小鼠中 Gal-3 的表达早在 3 个月大时就显着增加，并且抗 Aβ 寡聚化被认为可以防止 Aβ 毒性，因此 Gal-3 可被视为对抗 AD 的新治疗靶点。
Amyloid-beta (A beta) oligomers largely initiate the cascade underlying the pathology of Alzheimer's disease (AD). Galectin-3 (Gal-3), which is a member of the galectin protein family, promotes inflammatory responses and enhances the homotypic aggregation of cancer cells. Here, we examined the role and action mechanism of Gal-3 in A beta oligomerization and A beta toxicities. Wild-type (WT) and Gal-3-knockout (KO) mice, APP/PS1;WT mice, APP/PS1;Gal-3(+/-) mice and brain tissues from normal subjects and AD patients were used. We found that A beta oligomerization is reduced in Gal-3 KO mice injected with A beta, whereas overexpression of Gal-3 enhances A beta oligomerization in the hippocampi of Ac-injected mice. Gal-3 expression shows an age-dependent increase that parallels endogenous A beta oligomerization in APP/PS1 mice. Moreover, A beta oligomerization, Ibal expression, GFAP expression and amyloid plaque accumulation are reduced in APP/ PS1;Gal-3(+/-) mice compared with APP/PS1;WT mice. APP/PS1;Gal-3(+/-) mice also show better acquisition and retention performance compared to APP/PS1;WT mice. In studying the mechanism underlying Gal-3-promoted A beta oligomerization, we found that Gal-3 primarily co-localizes with Iba1, and that microglia-secreted Gal-3 directly interacts with A beta. Gal-3 also interacts with triggering receptor expressed on myeloid cells-2, which then mediates the ability of Gal-3 to activate microglia for further Gal-3 expression Immunohistochemical analyses show that the distribution of Gal-3 overlaps with that of endogenous A beta in APP/PS1 mice and partially overlaps with that of amyloid plaque. Moreover, the expression of the A beta-degrading enzyme, neprilysin, is increased in Gal-3 KO mice and this is associated with enhanced integrin-mediated signaling. Consistently, Gal-3 expression is also increased in the frontal lobe of AD patients, in parallel with A beta oligomerization. Because Gal-3 expression is dramatically increased as early as 3 months of age in APP/PS 1 mice and anti-A beta oligomerization is believed to protect against A beta toxicity, Gal-3 could be considered a novel therapeutic target in efforts to combat AD.