神经免疫文献阅读第3期：Immunity—哈佛医学院揭示APOE4通过抑制小胶质细胞激活以预防青光眼中RGC的变性

中文摘要

载脂蛋白E4（APOE4）等位基因与阿尔茨海默病风险增加和青光眼风险降低相关，但其潜在机制尚不清楚。在这里，科学家在两个小鼠青光眼模型中发现，小胶质细胞转变为神经退行性表型，其特征是Apoe和Lgals3（Galectin-3）的上调，这两个基因的表达在人类青光眼患者的视网膜中也上调。尽管眼内压（IOP）升高，但小胶质细胞特异性靶向缺失Apoe或携带人类APOE4等位基因仍可免受视网膜神经节细胞（RGC）丢失的影响。与Apoe-/-视网膜小胶质细胞相似，表达APOE4的小胶质细胞在眼压升高后不会上调神经变性相关基因，包括Lgals3。Galectin-3的遗传和药理学靶向抑制可改善RGC变性，Galectin-3在人APOE4青光眼样本中的表达减弱。这些结果表明，APOE4+小胶质细胞的活化抑制对青光眼具有保护作用，APOE-Gallectin-3信号通路可作为治疗这种致盲性疾病的靶点。

英文摘要

The apolipoprotein E4 (APOE4) allele is associated with an increased risk of Alzheimer disease and a decreased risk of glaucoma, but the underlying mechanisms remain poorly understood. Here, we found that in two mouse glaucoma models, microglia transitioned to a neurodegenerative phenotype characterized by upregulation of Apoe and Lgals3 (Galectin-3), which were also upregulated in human glaucomatous retinas. Mice with targeted deletion of Apoe in microglia or carrying the human APOE4 allele were protected from retinal ganglion cell (RGC) loss, despite elevated intraocular pressure (IOP). Similarly to Apoe-/- retinal microglia, APOE4-expressing microglia did not upregulate neurodegeneration-associated genes, including Lgals3, following IOP elevation. Genetic and pharmacologic targeting of Galectin-3 ameliorated RGC degeneration, and Galectin-3 expression was attenuated in human APOE4 glaucoma samples. These results demonstrate that impaired activation of APOE4 microglia is protective in glaucoma and that the APOE-Galectin-3 signaling can be targeted to treat this blinding disease.

参考文献：Apolipoprotein E4 impairs the response of neurodegenerative retinal microglia and prevents neuronal loss in glaucoma. Immunity. 2022 Sep 13;55(9):1627-1644.e7. doi: 10.1016/j.immuni.2022.07.014. Epub 2022 Aug 16.

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