Abstract
Presentation Description :
Microglia are dynamic guardians of neural tissue and the resident immune cells of the central nervous system. The disease-associated microglial signature (DAM), also known as the microglial neurodegenerative phenotype (MGnD), has gained significant attention in recent years as a fundamental microglial response common to various neurodegenerative disease pathologies, including glaucoma. One of the genes upregulated in microglia in glaucoma is Apoe, the major lipoprotein in the brain that as APOE4 allele increases the risk of Alzheimer’s disease but decreases the risk of glaucoma. We demonstrate that Apoe is the key upstream regulator of the microglial cytotoxic response in glaucoma, while a secreted molecule called Galectin-3 is an important effector that can be targeted genetically and pharmacologically to prevent RGC loss in glaucoma. Furthermore, APOE and Galectin-3 are upregulated in the retinal samples and the aqueous humor of glaucoma patients. We also demonstrate that APOE4 allele acts similarly to Apoe loss-of-function in terms of impaired microglial activation and improved RGC survival despite elevated intraocular pressure, explaining why this allele is associated with a decreased risk of human glaucoma. This finding may have important mechanistic and therapeutic implications for other neurodegenerative diseases, including Alzheimer’s disease.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.