Abstract
Purpose :
Microglia responses occur early in the pathogenesis of glaucoma and other neurodegenerative diseases. Previous work revealed that global reduction of microglia leads to increased susceptibility for optic nerve damage in an ocular hypertension (OHT) model. In recent years, changes in microglial states have been correlated with later glaucoma severity; however, their specific role(s) are not known. In the brain, disease associated microglia (DAM) depends on TREM2 signaling and is suggested to be neuroprotective but has not been investigated in glaucoma. We hypothesize that genetically ablating Trem2, preventing DAM formation, in an inducible OHT model will alter glaucomatous optic nerve damage differentially from global microglia depletion.
Methods :
Microglia were depleted in 9.5 months old (mo) DBA/2J mice (D2), a chronic model of OHT, using dietary PLX5622, a CSF1R inhibitor. Intraocular pressures (IOPs) were measured. At 12mo, optic nerves were evaluated for glaucomatous damage using p-phenylenediamine staining (n>12 per diet). Retinas corresponding to the assessed optic nerves were isolated for confocal microscopy (n=6 per diet). To test the role of TREM2, acute OHT was induced in Trem2 deficient (knockout, KO) and sufficient (wild type, WT) C57BL/6J (B6) mice using an intracameral injection of photopolymerizing biomatrix (HAMA). IOPs were measured, and optic nerves and retinas evaluated as described above.
Results :
D2 mice exposed to PLX5622 for 10 weeks showed 75% depletion of retinal microglia. PLX5622 treatment did not appear to affect IOP. However, analysis of optic nerves showed a significant PLX5622 diet-associated increase in moderate to severe optic nerve damage compared to controls (p= 0.0022). Initial analysis of optic nerves from Trem2-KO and Trem2-WT HAMA mice revealed Trem2 deficiency lessened susceptibility to OHT-induced optic nerve damage (p<0.0001).
Conclusions :
Our results indicate that reducing the retinal microglial population from 9.5 to 12mo increased susceptibility for glaucomatous neurodegeneration in D2 mice. This suggests an overall beneficial effect of microglia in glaucoma. Yet, genetic ablation of Trem2, a gene shown to be involved in activation of microglia to the ‘DAM’ state, appeared neuroprotective. While further investigation is still required, our data suggest targeting specific states of microglia is a promising avenue to explore for treatments of glaucoma.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.