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Human induced pluripotent stem cell-derived microglia with a CX3CR1-V249I genetic variant exhibit dysfunctional

Kaylee D Tutrow1,2, Jade Harkin2,3, Laurna Varghese1,2

  • 1Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis IN 46202.

Biorxiv : the Preprint Server for Biology
|July 9, 2025
PubMed

Insights

The CX3CR1-V249I variant impairs human microglia-like cell function, increasing neurodegeneration risk. This variant affects cell death, amyloid-beta uptake, and neuronal health, highlighting CX3CR1

Area of Science:

  • Neuroscience
  • Immunology
  • Genetics

Background:

  • Microglia play a key role in neurodegenerative diseases.
  • Genetic risk factors are often linked to microglial function.
  • Fractalkine receptor (CX3CR1) signaling is crucial for microglial activity.

Purpose of the Study:

  • To investigate the functional consequences of the CX3CR1-V249I single nucleotide polymorphism (SNP) in human microglia.
  • To explore the impact of this variant on microglial function and neuronal health.

Main Methods:

  • Generation of induced pluripotent stem cell (iPSC)-derived human microglia-like cells (hMGLs) carrying the CX3CR1-V249I variant.
  • Assessment of microglial functions including cell death, amyloid-beta uptake, morphology, and migration.
  • Co-culture experiments with neurons to evaluate neuro-microglial interactions.

Main Results:

  • The CX3CR1-V249I variant increased susceptibility to starvation-induced cell death in hMGLs.
  • Amyloid-beta uptake, microglial morphology, and migration were impaired by the CX3CR1-V249I variant.
  • hMGLs with the variant induced abnormal neuronal growth and hyperexcitability in co-culture systems.

Conclusions:

  • The CX3CR1-V249I variant significantly impairs human microglial function.
  • This microglial dysfunction, driven by the V249I variant, contributes to pathogenic states relevant to neurodegeneration.
  • CX3CR1 signaling and its variants are critical therapeutic targets for neurodegenerative diseases.

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