# Investigating the role of the fractalkine axis in Alzheimer's Disease pathology using human induced pluripotent stem cells

> **NIH NIH F30** · INDIANA UNIVERSITY INDIANAPOLIS · 2024 · $38,692

## Abstract

PROJECT SUMMARY/ABSTRACT
Alzheimer’s Disease (AD) is the most common form of dementia and is a neurodegenerative disease
characterized by the accumulation of toxic amyloid beta (Aβ) and subsequent aggregation of
hyperphosphorylated tau. Microglia are the resident immune cells of the central nervous system, which
function to support neurons, remove debris, and modulate neuronal viability, among other functions. Signaling
through the CX3CR1/CX3CL1 axis between microglia and neurons modulates microglial function and
reactivity, and previous studies have shown that communication through this axis is essential in the
maintenance of homeostatic conditions within the central nervous system, while disruptions have been
associated with neurodegeneration. The microglial CX3CR1 receptor interacts selectively with CX3CL1
secreted by neurons to modulate inflammation, with previous studies demonstrating that gene variants in
CX3CR1 are associated with neurodegeneration observed in AD. However, the mechanisms by which affected
microglia lead to neurodegeneration in AD remain unclear, and these prior studies have primarily utilized
murine models. While many advancements in the understanding of AD pathogenesis have been established
through modeling the disease in mice, these models have failed to produce a clinically relevant therapeutic for
AD patients. As such, there is a critical need to develop complimentary models that may account for at least
some of these species-specific differences. Human induced pluripotent stem cells (iPSCs) can be differentiated
into all cell types of the brain, with the possibility to establish novel co-culture models to accurately assess
interactions between critical cell types, including the analysis of disease-associated gene variants and how
they lead to neurodegeneration. Thus, the central goal of this application is to utilize iPSCs to investigate the
role of the CX3CR1 V249I variant in microglial function and whether this variant induces a neurodegenerative
phenotype in neurons. To accomplish this, in Aim 1, I will investigate the impact of the CX3CR1 V249I variant
on iPSC-derived microglia alone by assessing features including inflammatory signaling, phagocytosis, and
RNA sequencing. In Aim 2, I will determine whether interactions with V249I microglia mediate altered
phenotypes and function in neurons using both 2D and 3D co-culture systems, as well as how neurons may
further modulate disease phenotypes in microglia. I hypothesize that the CX3CR1 V249I variant will cause a
dysfunctional phenotype in microglia, and that this will mediate phenotypic and functional changes to neurons
in either a cell autonomous or non-cell autonomous manner. It is expected that this work has the potential to
identify mechanisms by which a genetic variant modulates neurodegenerative pathology related to AD. Taken
together, this proposal provides an innovative approach to investigating the pathophysiology of genetic
variants related to AD in a nov...

## Key facts

- **NIH application ID:** 10903203
- **Project number:** 1F30AG084304-01A1
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Kaylee Tutrow
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $38,692
- **Award type:** 1
- **Project period:** 2024-05-27 → 2027-05-26

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10903203

## Citation

> US National Institutes of Health, RePORTER application 10903203, Investigating the role of the fractalkine axis in Alzheimer's Disease pathology using human induced pluripotent stem cells (1F30AG084304-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10903203. Licensed CC0.

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