# Gas6:Axl regulation of microglia immune function and Alzheimer's pathogenesis

> **NIH NIH R56** · UNIVERSITY OF ROCHESTER · 2020 · $512,965

## Abstract

The distinct pathology of AD includes extracellular deposits of amyloid-b (Ab), intracellular accumulation of
hyperphosphorylated tau protein, and wide-spread neuroinflammation. Despite genetic evidence that Ab drives
Alzheimer’s disease (AD) pathology, efforts to intervene with immunotherapies and secretase inhibitors have
essentially all failed, indicating that the amyloid hypothesis is not sufficient to explain the full pathological course.
Instead, accumulating evidence reveals an intertwining of these three pathologies, which together drive the
synaptic loss and neural disconnection that lead to dementia. Our work and that of others supports a model in
which neuroinflammation links amyloid and tau pathology, and can directly contribute to synaptic loss, vascular
dysfunction, and oxidative damage. Microglia are essential drivers of neuroinflammation that show dramatic
phenotypic changes in neurodegenerative diseases and express disease-associated microglial (DAM) genes,
including some recognized as risk factors for AD (e.g. TREM2 and ApoE). Thus, targeting microglial activation
represents an important potential therapeutic approach to AD and other neurodegenerative conditions. One
identified DAM is Axl, a receptor tyrosine kinase that is upregulated in AD, particularly in microglia associated
with amyloid plaques. Binding of Axl’s ligand, growth-arrest specific protein 6 (Gas6) has multimodal effects that
include both initiation of phagocytosis and suppression of inflammation. Despite the association of Axl-
expressing microglia with amyloid deposits, Axl’s role in Ab phagocytosis is not known, nor is it known whether
microglial Axl signaling modifies the inflammatory environment and other AD pathologies such as tau. Based on
our preliminary studies, we hypothesize that activation of Axl signaling with Gas6 can be used to increase Ab
phagocytosis and suppress inflammation, providing a beneficial effect on other disease-associated endpoints
such as tau phosphorylation and cognitive dysfunction. This idea, and the corollary hypothesis that loss of Axl
signaling increases AD pathology, will be tested in APP/PS1 and P301S tau mice as well as in primary microglial
cultures using genetic and pharmacologic approaches. Our proposed experiments will provide fundamental
information about the role of Gas6:Axl signaling in microglia, and help determine whether modulating Axl activity
provides a tractable therapeutic approach for AD using preclinical models.

## Key facts

- **NIH application ID:** 10229210
- **Project number:** 1R56AG066397-01
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** Michael Rusty Elliott
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $512,965
- **Award type:** 1
- **Project period:** 2020-09-15 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10229210

## Citation

> US National Institutes of Health, RePORTER application 10229210, Gas6:Axl regulation of microglia immune function and Alzheimer's pathogenesis (1R56AG066397-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10229210. Licensed CC0.

---

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