# Modulating microglial phagocytosis and inflammation in Alzheimer's disease: investigating a role for Axl

> **NIH NIH F30** · UNIVERSITY OF ROCHESTER · 2021 · $45,986

## Abstract

Project Abstract
 Alzheimer’s disease (AD) is the leading cause of dementia and is characterized by the accumulation of
amyloid species into extracellular plaque as well as hyperphosphorylated intracellular tau tangles. Microglia,
the immune cells of the brain, play a critical role in clearance of amyloid species via phagocytosis and
contribute to neuroinflammation in AD via the production of inflammatory cytokines. Thus, understanding the
molecular mechanisms that facilitate microglial phagocytosis and suppression of inflammation will be critical to
developing highly targeted therapies. Our lab and others have observed a robust increase in expression of the
Axl receptor on microglia directly surrounding amyloid plaque. Axl, a receptor tyrosine kinase, is a lucrative
target to study in the context of AD due to its downstream signaling that includes both initiation of phagocytosis
and activation of transcription factors suppressing the production of proinflammatory cytokines. However, there
is a distinct paucity of literature examining the role of Axl in microglia and in the context of AD. I hypothesize
that activation of Axl drives microglial phagocytosis of amyloid species and reduces the inflammatory
environment around plaque in AD.
 Aim 1 will utilize in vitro techniques to explore phagocytosis of amyloid species using multiple microglial
cell lines during stimulation with the Axl ligand, Gas6, and inhibition with the small molecule Axl inhibitor, R428.
Aim 2 seeks to explore my hypothesis using overexpression of Gas6 via an adeno-associated viral vector in
transgenic AD mice as well as chronic injections of the Axl inhibitor BMS-777607. Behavioral outcomes,
amyloid plaque burden, extent of microglial phagocytosis of amyloid, and cytokine production will be quantified.
Based on our data and the current literature, I hypothesize that activation of Axl using Gas6 will decrease
plaque burden via increased microglial phagocytosis of plaque while simultaneously decreasing the
inflammatory environment, and that administration of the Axl inhibitor will produce decreased microglial
phagocytosis and increased production of proinflammatory cytokines.
 Together, the experimental results generated by these aims will contribute to understanding the role of
microglia as mediators of amyloid clearance and regulation of inflammation in AD. The breadth of techniques
required to complete these aims, as well as the clinical experience, professional development activities, and
opportunity for inter- and intra-institutional collaboration as described in my training plan will provide me with
excellent training to help me attain my goal of becoming a physician-scientist in the field of neurodegeneration.

## Key facts

- **NIH application ID:** 10232159
- **Project number:** 5F30AG061939-03
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** Laura Owlett
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $45,986
- **Award type:** 5
- **Project period:** 2019-08-01 → 2022-05-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10232159

## Citation

> US National Institutes of Health, RePORTER application 10232159, Modulating microglial phagocytosis and inflammation in Alzheimer's disease: investigating a role for Axl (5F30AG061939-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10232159. Licensed CC0.

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