University of Alberta
Medical Genetics

Author Of 1 Presentation

Neuroprotection, Regeneration and/or Remyelination Late Breaking Abstracts

LB1186 - Investigating fractalkine as a potential remyelination therapy in the cuprizone MS mouse model (ID 1983)

Presentation Number
LB1186
Presentation Topic
Neuroprotection, Regeneration and/or Remyelination

Abstract

Background

We have previously discovered that a certain type of neurons, inhibitory interneurons, secrete cytokine fractalkine (FKN), which regulates oligodendrocyte formation from embryonic cortical oligodendrocyte precursor cells (OPCs) during brain development (Voronova et al. 2017 Neuron).

Objectives

Here, we aimed to analyze whether administration of exogenous FKN after demyelination injury may engage OPCs to enhance remyelination in the adult mouse brain.

Methods

We utilized single-cell RNA fluorescent in situ hybridization (RNA scope) to detect FKN receptor CX3CR1 expression in demyelinated murine brain. We also injected FKN directly conjugated to fluorophore Alexa-647 (FKN-647) to identify which cell types bind FKN in vivo. We then infused FKN into the lateral ventricle of cuprizone-demyelinated brains to test the effect of exogenous FKN infusion on remyelination. To determine the mechanism of FKN-mediated remyelination, murine primary microglia-free OPCs or isolated microglia were incubated in the presence of vehicle-control or FKN and analyzed for differences in proliferation, differentiation, survival, migration, and/or phagocytosis. Finally, to determine if FKN signalling is necessary for oligodendrocyte genesis, microglia-free OPCs were incubated in the presence of FKN or CX3CR1 function blocking antibodies.

Results

We show that FKN receptor Cx3cr1 mRNA is expressed in OPCs in the adult demyelinated brain, in addition to microglia; moreover, FKN-647 injected into the lateral ventricle of the adult murine brain diffuses into the tissue and binds OPCs and microglia. Our initial data suggest FKN infusion into cuprizone demyelinated brains may increase formation of new oligodendrocytes in vivo in both male and female brains. Microglia-free OPC culture experiments demonstrate FKN signalling is sufficient for OPC migration and survival and necessary for oligodendrocyte differentiation. Finally, exogenous FKN may increase myelin debris phagocytosis by both OPCs and microglia. We are currently investigating how FKN affects microglia-OPC cell-to-cell communication during remyelination.

Conclusions

Our studies address the exciting possibility of remyelination therapies in MS using the candidate therapeutic FKN, and reveal FKN may directly regulate OPC function for enhanced remyelination in a demyelinated brain.

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