# The Role of APOE Signaling in Microglia in Glaucoma

> **NIH NIH K08** · MASSACHUSETTS EYE AND EAR INFIRMARY · 2021 · $234,328

## Abstract

This proposal describes a 3-year training program for the development of an academic career focused on
understanding the role of retinal neuroinflammation in glaucoma. My research goal is to elucidate the role of
microglia, resident immune cells in the retina and the brain, in the pathogenesis of glaucoma. Our preliminary
data demonstrate that in the microbead glaucoma model, microglia suppress homeostatic genes and induce a
disease-associated molecular signature (MGnD), which is shared with brain neurodegenerative diseases. In
addition to the induction of proinflammatory cytokines and neurotoxic substances, MGnD microglia also
significantly upregulate production of APOE, the major lipoprotein in the brain. APOE has recently been found
to critically regulate MGnD molecular signature in brain microglia, and is genetically linked to Alzheimer’s
disease, age-related macular degeneration, and glaucoma. Furthermore, we have found that mice in which
APOE has been targeted only in myeloid cells (microglia and peripheral monocytes/macrophages) are protected
from microbead-induced glaucoma. We hypothesize that APOE controls the switch of retinal microglia from
homeostatic to a harmful neurodegenerative phenotype, and that in the absence of APOE, microglia remain in
the homeostatic state, leading to a decreased retinal neuroinflammatory response and RGC degeneration
following intraocular pressure (IOP) elevation. We will address this hypothesis in the following specific aims:
1) Determine the functional impact of microglia-specific APOE targeting in glaucoma. In this aim, we will
address whether selective ablation of APOE in microglia utilizing tamoxifen-inducible Cx3cr1-CreERT2 APOEfl/fl
mice leads to behavioral and functional neuroprotection after IOP induction, as assessed by optokinetic
response, electroretinogram, and visual evoked potential testing.
2) Investigate the mechanism by which APOE signaling contributes to glaucoma pathogenesis. We will
investigate the hypothesis that targeting APOE in microglia maintains these cells in the homeostatic state,
resulting in decreased apoptotic neuron phagocytosis and cytokine production.
3) Characterize the role of human APOE isoforms in the mouse model of glaucoma. By using novel
humanized-floxed APOE e2, e3 and e4 mice, we will investigate the hypothesis that mice with APOE e4 allele
exhibit an altered microglial molecular signature and are less susceptible to RGC loss after microbead-induced
IOP elevation.
The research outlined in this proposal will serve to investigate the role of APOE signaling in microglia in
glaucoma, with the ultimate goal of developing novel neuroprotective treatments for this common blinding
disease. This research addresses an understudied area of neuroinflammation in glaucoma while also preparing
me for a successful career as an independent clinician-scientist.

## Key facts

- **NIH application ID:** 10238886
- **Project number:** 5K08EY030160-03
- **Recipient organization:** MASSACHUSETTS EYE AND EAR INFIRMARY
- **Principal Investigator:** Milica Margeta
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $234,328
- **Award type:** 5
- **Project period:** 2019-09-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10238886

## Citation

> US National Institutes of Health, RePORTER application 10238886, The Role of APOE Signaling in Microglia in Glaucoma (5K08EY030160-03). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10238886. Licensed CC0.

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