# Regulation of microglial function by blood-borne factors

> **NIH NIH F31** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2024 · $47,374

## Abstract

Project Summary: Age-related disorders such as Alzheimer’s disease (AD) present urgent issues to the aging
population. Given the lack of universally effective treatments, novel approaches must be developed to reduce
the impact of aging, the greatest risk factor for development of AD. Recent work has shown rejuvenation of age-
sensitive organs, including the brain, through exposure to young blood. Our lab identified a loss of tissue
inhibitor of metalloproteinase 2 (TIMP2) expression with age, and its restoration is critical in mediating the
rejuvenating effects of young blood in aged animals. Despite these findings, the precise mechanism and cellular
targets of TIMP2 have yet to be identified. It is currently unknown whether the positive effects of TIMP2 in aging
generalize to the context of AD pathology. However, aging and AD present similar environmental challenges to
the brain (e.g., inflammation, cellular debris from dying cells, toxic proteins). Based on the role of microglia in
rapidly responding to debris (e.g., dying cells, amyloid, etc), we hypothesize that TIMP2 modulates microglial
function. Consistent with this hypothesis, we have found that treatment with TIMP2 reduces microglial activation
in the aged brain. Upon exposure to the debris of aging and AD, a subset of microglia acquires a disease-
associated microglia (DAM) phenotype to respond to these challenges. This phenotype is initially protective by
allowing microglia to effectively respond to environmental challenges, but unbridled activation can cause
dysfunction or senescence of microglia and damage to surrounding tissue. Restoration of an effective response
to debris may be critical to limit pathology. TIMP2 has been found to be a marker of the DAM transcriptional
profile, and our preliminary data indicate that cell-intrinsic TIMP2 can regulate microglial state. This proposal
aims to characterize microglial response to TIMP2 treatment and the cell-intrinsic role of microglial TIMP2 in
enabling an effective response to debris in differing pathological contexts. Aim 1 will assess the morphological
and inflammatory responses of microglia following treatment with TIMP2 in aged and AD pathological contexts
to determine how microglia respond to damage following treatment. Furthermore, we will examine microglial-
neuronal interactions in hippocampus using super-resolution microscopy and RNAscope. To probe the cell-
intrinsic role of microglial TIMP2, Aim 2 will test the hypothesis that microglial TIMP2 rejuvenates response to
aging and AD-associated pathology. We developed a mouse model that allows us to conditionally delete TIMP2
within microglia in diverse contexts. Upon deletion, we will examine response to debris by analyzing changes in
pathology, morphology, cytokine release, and microglia-neuron interactions. The innovative methods employed
in this proposal will provide insights into the role of TIMP2 acting as an extracellular protein on the function of
microglia, while also ...

## Key facts

- **NIH application ID:** 10900443
- **Project number:** 5F31AG079604-02
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** Brittany Marie Hemmer
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $47,374
- **Award type:** 5
- **Project period:** 2023-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10900443

## Citation

> US National Institutes of Health, RePORTER application 10900443, Regulation of microglial function by blood-borne factors (5F31AG079604-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10900443. Licensed CC0.

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