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Apolipoprotein E4 impairs the response of neurodegenerative retinal microglia and prevents neuronal loss in glaucoma
Milica A Margeta1, Zhuoran Yin2, Charlotte Madore3
1Ann 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.
Abstract:
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.
Insights
The apolipoprotein E4 (APOE4) allele protects against glaucoma by altering microglial function. Targeting APOE-Galectin-3 signaling may offer new treatments for this blinding disease.
Area of Science:
- Neuroscience
- Ophthalmology
- Immunology
Background:
- The apolipoprotein E4 (APOE4) allele is linked to Alzheimer's disease risk and glaucoma protection.
- Mechanisms behind APOE4's effect on glaucoma are not fully understood.
Purpose of the Study:
- To investigate the role of microglia and APOE in glaucoma pathogenesis.
- To explore the APOE-Galectin-3 pathway as a therapeutic target for glaucoma.
Main Methods:
- Utilized mouse models of glaucoma with elevated intraocular pressure (IOP).
- Examined microglial phenotypes, including Apoe and Lgals3 (Galectin-3) expression.
- Assessed retinal ganglion cell (RGC) survival in mice with targeted Apoe deletion or human APOE4 expression.
- Investigated the effects of genetic and pharmacologic Galectin-3 inhibition.
Main Results:
- Microglia in mouse glaucoma models upregulated Apoe and Lgals3, mirroring human glaucomatous retinas.
- Mice lacking microglial Apoe or expressing human APOE4 showed protection against RGC loss despite high IOP.
- APOE4-expressing microglia did not upregulate neurodegenerative genes like Lgals3 after IOP elevation.
- Targeting Galectin-3 reduced RGC degeneration and was attenuated in human APOE4 glaucoma samples.
Conclusions:
- Impaired activation of APOE4 microglia is protective in glaucoma.
- The APOE-Galectin-3 signaling pathway presents a potential therapeutic target for treating glaucoma and preventing blindness.
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