# Mechanisms that regulate microglial dynamics in the context of plasticity (Supplement)

> **NIH NIH R01** · UNIVERSITY OF ROCHESTER · 2021 · $385,000

## Abstract

Project Summary
Alzheimer's disease (AD) is the most common age-related dementia, accounting for the progressive cognitive
impairment and compromised life quality of approximately 5.8 million people in the United States. AD is
characterized by neuroinflammation and microglia have a complex role in both the early and late stages of the
disease. AD is also characterized by dysregulation of norepinephrine (NE) signaling, degeneration of
noradrenergic neurons in the locus coeruleus (LC) and sleep disturbances that further alter normal patterns of
NE release. Signaling through β2 adrenergic receptors (β2 ARs) has been shown to be anti-inflammatory and to
alter microglial behavior in the context of AD, although its effects on AD pathology have been controversial and
the details of NE signaling to microglia have not been defined. In this supplement proposal, we will build on the
aims of the parent RO1 in which we have discovered that endogenous NE signaling to microglia through
microglial β2 ARs reduces the size of the microglial arbor and inhibits microglial surveillance of the brain, limiting
microglial interactions with neurons and impairing experience-dependent plasticity. Based on this work, we
believe that the normal patterns of NE release that fluctuate as a function of arousal state allow microglia to cycle
through “active” and “passive” states. When NE release is blunted due to LC neuron degeneration or sleep
disruption in AD, microglia no longer cycle through these different states. This alters their behavior and impacts
their ability to interact with amyloid deposits, protect synapses from elimination, and respond appropriately to
cues in their environment. The work presented in this supplement will generate preliminary data to show how β2
AR signals are altered in microglia over time in a mouse model of AD, and how this correlates with AD pathology.
We will also determine how long-term periodic pharmacological stimulation of β2 AR signaling alters microglial
dynamics and AD pathology to set the stage for future experiments where we use microglial specific knock out
of β2 ARs to test the contribution of microglia in this context. Lastly, we will use these microglial specific β2 AR
KO mice, in the absence of AD pathology, to determine whether long-term loss of β2 AR signaling in microglia
alters inflammatory responses. These aims are highly synergistic with those of the parent R01 and have clear
relevance to AD. Together they will generate supporting data for a future grant application built on our broad
hypothesis that cyclical stimulation of microglial β2 ARs is critical for the maintenance of microglial
responses that are beneficial in the context of AD pathology.

## Key facts

- **NIH application ID:** 10286201
- **Project number:** 3R01NS114480-02S1
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** Anna K Majewska
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $385,000
- **Award type:** 3
- **Project period:** 2020-01-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10286201

## Citation

> US National Institutes of Health, RePORTER application 10286201, Mechanisms that regulate microglial dynamics in the context of plasticity (Supplement) (3R01NS114480-02S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10286201. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*