Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA.
Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Immunity. 2022 Sep 13;55(9):1627-1644.e7. doi: 10.1016/j.immuni.2022.07.014. Epub 2022 Aug 16.
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有关，但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，小胶质细胞向具有神经退行性表型的细胞转变，其特征是 Apoe 和 Lgals3（半乳糖凝集素 3）的上调，而人类青光眼视网膜中也上调了这些基因。在小胶质细胞中靶向敲除 Apoe 或携带人 APOE4 等位基因的小鼠尽管眼压升高，但其视网膜神经节细胞 (RGC) 损失得到了保护。与 Apoe 视网膜小胶质细胞类似，APOE4 表达的小胶质细胞在眼压升高后并未上调神经退行性相关基因，包括 Lgals3。Galectin-3 的遗传和药物靶向治疗改善了 RGC 变性，并且在人 APOE4 青光眼样本中 Galectin-3 的表达减弱。这些结果表明，APOE4 小胶质细胞的激活受损在青光眼中有保护作用，并且可以针对 APOE-Galectin-3 信号通路来治疗这种致盲疾病。
