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.

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，但其潜在机制仍知之甚少。在这里，我们发现在两种小鼠青光眼模型中，小胶质细胞转变为神经退行性表型，其特征是Apoe和Lgals3 (Galectin-3)上调，这在人类青光眼视网膜中也上调。尽管眼压 (IOP) 升高，但在小胶质细胞中靶向删除Apoe或携带人类APOE4等位基因的小鼠仍能免受视网膜神经节细胞 (RGC) 损失。与Apoe ^−/−视网膜小胶质细胞类似，表达APOE4的小胶质细胞在 IOP 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可改善 RGC 变性，并且人APOE4青光眼样本中 Galectin-3 的表达减弱。这些结果表明， APOE4小胶质细胞活化受损对青光眼具有保护作用，并且可以靶向 APOE-Galectin-3 信号传导来治疗这种致盲性疾病。