期刊
IMMUNITY
卷 55, 期 9, 页码 1627-+出版社
CELL PRESS
DOI: 10.1016/j.immuni.2022.07.014
关键词
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类别
资金
- Cure Alzheimer's Fund
- BrightFocus Foundation [2020A016806]
- NIH/NINDS [R01 NS088137]
- NIH/NIA [R01 AG051812, R01 AG054672]
- NIH/NEI [R01 EY027921, K12 EY016335, K08 EY030160, EY025913, EY025259, 5K23EY026988, P30EY03790]
- American Glaucoma Society Young Clinician Scientist Award
- Research to Prevent Blindness Career Development Award
- Robert M. Sinskey Foundation
- Ruettgers Family Charitable Foundation
- B.L. Manger Foundations
- National Multiple Sclerosis Society [5092A1]
- National Health and Medical Research Council Australia [RG180378]
- Nancy Davis Foundation innovative Award
- Amyotrophic Lateral Sclerosis Association Award
- Massachusetts Eye and Ear Summit Fund
- Research to Prevent Blindness Ernest & Eliza-beth Althouse Special Scholar Award
- [R01 GM132668]
- [R01 AG075509]
- [R21 NS104609]
- [R21 NS101673]
This study shows that the APOE4 allele has a neuroprotective effect in glaucoma by impairing the activation of microglia. Additionally, targeting the APOE4-Galectin-3 signaling pathway may be a potential therapeutic approach for glaucoma.
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.
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