# Targeting neuroinflammation in AD with novel CX3CR1 agonists

> **NIH NIH R01** · SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE · 2021 · $677,072

## Abstract

PROJECT SUMMARY
 Fractalkine protein (FKN, CX3CL1) suppresses microglial activation leading to decreased
neurodegeneration in a number of neurological disorders, including Alzheimer's disease (AD). In AD, a large
reduction in FKN has been observed in postmortem cortical tissue. We have studied FKN and its role in
neurodegeneration extensively, and we have demonstrated a beneficial effect of FKN in multiple
neurodegenerative disease models. Our work demonstrates that overexpression of a soluble form of FKN
(sFKN) decreases tau pathology in Tg4510 mice. More importantly, we observed that sFKN significantly reduces
brain atrophy and neuron loss in these mice. In Parkinson's disease (PD) mouse models, overexpression of
sFKN, but not a cleavage-resistant, insoluble mutant FKN, reduces disease pathology and neuron loss. Positive
activity with soluble versus membrane-bound FKN suggests that a soluble molecule has the potential to activate
the receptor and achieve neuroprotective effects. These observations prompted the hypothesis that the FKN
pathway could be exploited as a therapeutic approach to treat AD.
 High-throughput screening produced a series of chemical scaffolds that are novel small molecule agonists
of CX3CR1 suitable for further optimization through this funding opportunity. The lead compound is potent and
highly selective, and has been shown to reduce LPS-mediated activation of microglia. Here, we propose to
develop orally bioavailable potent CX3CR1 agonist compounds suitable for use as chemical probes. This
campaign leverages the unique resources of Sanford Burnham Prebys and USF Health. Chemistry efforts will
refine the current lead compound to improve potency and selectivity, and enhance the compound's drug-like
properties. These efforts are supported by a robust testing funnel consisting of cellular and biochemical assays
of CX3CR1 signaling, as well as appropriate counter-screens. The physicochemical and pharmacological
properties of the compounds will be optimized, followed by pharmacokinetic studies in rodents. We will test for
target engagement and efficacy in the AD animal models, in which we will identify at least one CX3CR1 agonist
with potent efficacy in vivo.

## Key facts

- **NIH application ID:** 10158381
- **Project number:** 5R01AG062557-03
- **Recipient organization:** SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
- **Principal Investigator:** Kevin Ron Nash
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $677,072
- **Award type:** 5
- **Project period:** 2019-05-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10158381

## Citation

> US National Institutes of Health, RePORTER application 10158381, Targeting neuroinflammation in AD with novel CX3CR1 agonists (5R01AG062557-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10158381. Licensed CC0.

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