美国哈佛大学医学院Oleg Butovsky团队近期取得重要工作进展，他们研究发现了载脂蛋白E4损害神经退行性视网膜小胶质细胞的反应并防止青光眼的神经元损失。该项研究成果2022年8月16日在线发表于《免疫》杂志上。

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，但其潜在机制仍知之甚少。研究人员发现在两个小鼠青光眼模型中，小胶质细胞转变为以Apoe和Lgals3（Galectin-3）上调为特征的神经退行性表型，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缺失Apoe或携带人类APOE4等位基因的小鼠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，在眼压升高后，表达APOE4的小胶质细胞不会上调神经退行性变相关基因，包括Lgals3。Galectin-3的遗传和药理学靶向改善了RGC病变，并且在人类APOE4青光眼样本中Galectin-3表达减弱。

这些结果表明，APOE4小胶质细胞的激活受损对青光眼具有保护作用，并且APOE-Galectin-3信号传导可以靶向治疗这种致盲疾病。

附：英文原文

Title: Apolipoprotein E4 impairs the response of neurodegenerative retinal microglia and prevents neuronal loss in glaucoma

Author: Milica A. Margeta, Zhuoran Yin, Charlotte Madore, Kristen M. Pitts, Sophia M. Letcher, Jing Tang, Shuhong Jiang, Christian D. Gauthier, Sebastian R. Silveira, Caitlin M. Schroeder, Eleonora M. Lad, Alan D. Proia, Rudolph E. Tanzi, David M. Holtzman, Susanne Krasemann, Dong Feng Chen, Oleg Butovsky

Issue&Volume: 2022-08-16

Abstract: The apolipoprotein E4 (APOE4) allele is associated with an increased risk of Alzheimer disease and a decreasedrisk of glaucoma, but the underlying mechanisms remain poorly understood. Here, wefound that in two mouse glaucoma models, microglia transitioned to a neurodegenerativephenotype characterized by upregulation of Apoe and Lgals3 (Galectin-3), which were also upregulated in human glaucomatous retinas. Mice withtargeted deletion of Apoe in microglia or carrying the human APOE4 allele were protected from retinal ganglion cell (RGC) loss, despite elevated intraocularpressure (IOP). Similarly to Apoe/ retinal microglia, APOE4-expressing microglia did not upregulate neurodegeneration-associated genes, includingLgals3, following IOP elevation. Genetic and pharmacologic targeting of Galectin-3 amelioratedRGC 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 betargeted to treat this blinding disease.

DOI: 10.1016/j.immuni.2022.07.014

Source: https://www.cell.com/immunity/fulltext/S1074-7613(22)00349-1