# MACROPHAGE MIR146B AND OCULAR NEOVASCULARIZATION

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2021 · $393,386

## Abstract

Macrophages are innate immune cells that are critically important as immune sensors and sentinels in
homeostasis. They also play pivotal roles in the development of age-induced diseases through their contribution
to repair and para-inflammation within tissues. Identifying the regulators that determine macrophage behavior has
tremendous potential for altering the course of diseases such as age-related macular degeneration
(AMD) and Alzheimer's disease (AD). With age, macrophages exhibit a pro-inflammatory phenotype characterized by
aberrant activation and altered polarization. This macrophage phenotype is often called ‘inflammaging’. Our laboratory has
demonstrated that the inability of aged macrophages to regulate inflammation and pathologic angiogenesis in the eye leads
to proliferative neovascularization and neurodegeneration, causes of catastrophic vision loss in AMD.
In the brain, as in the eye, resident macrophages called microglia are tasked with the crucial role of phagocytosis and
clearance of neurotoxic molecules during immunosurveillance. However, this natural defense mechanism is diminished
with aging and is especially deficient in neurodegenerative diseases such as AD, that cause dementia. Although the role of
microglia in AD has been extensively studied, the contributions of bone-marrow derived macrophages (BMDMs) to CNS
homeostasis in the context of aging and neurodegeneration is still limited. While in the healthy brain microglia operate
as the dominant immune cells that maintain CNS homeostasis, in the setting of age-associated para-inflammation
and neurodegenerative diseases such as AD, BMDMs are mobilized to the brain. Interestingly, BMDMs show a higher
phagocytic clearance of cerebral amyloid deposits than microglia and recruitment of BMDMs into the brain has been
demonstrated to significantly impact Amyloid beta (Aß) burden in AD models.
In an unbiased transcriptomic analysis, we recently identified macrophage miR146b as a ‘non-coding’ microRNA
(miR) that was significantly altered during aging. miR146b progressively declined with increasing age across all time
points examined in a robust pattern that was not seen with any other miR. Age-related and antagomir-mediated reduction
in miR146b led to decreased expression of IL1ß and CCL2, cytokines/chemokines critical in recruiting circulating
monocytes into the CNS in response to Aß accumulation. These data suggest that miR146b may be a ‘master regulator’ of
macrophage aging and a key molecule in the molecular pathogenesis of AD progression. Although the link between
neuro-inflammation and AD pathology is now well recognized, how the age-related molecular and functional
changes in BMDMs contribute to AD disease progression warrants further elucidation.
In this grant application, we propose to examine how the miR146b-regulated aging process in
macrophages alters their response to Aß and impacts AD-associated processes in the following specific aims:
Aim 1) Determine the impact of ma...

## Key facts

- **NIH application ID:** 10285203
- **Project number:** 3R01EY019287-08S1
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** RAJENDRA S APTE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $393,386
- **Award type:** 3
- **Project period:** 2010-09-30 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10285203

## Citation

> US National Institutes of Health, RePORTER application 10285203, MACROPHAGE MIR146B AND OCULAR NEOVASCULARIZATION (3R01EY019287-08S1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10285203. Licensed CC0.

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