# Microglial impact on remyelination

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2020 · $483,565

## Abstract

PROJECT SUMMARY
Enhancing remyelination is a critical strategy for restoring brain function after demyelination in multiple
sclerosis (MS) patients; however, despite concerted efforts, the ability to stimulate remyelination in MS brain
has remained elusive. While signaling pathways that promote oligodendrocyte precursor differentiation have
been identified, the experimental milieux under investigation do not replicate the mechanisms limiting
remyelination following MS-specific inflammatory CNS injuries. The current proposal builds on our new models
of demyelination/remyelination using pathogenic recombinant antibodies (rAbs) generated from MS patients.
Myelin-specific MS rAbs direct complement-mediated demyelination in vivo and ex vivo, all of which
spontaneously repair in association with microglial activation. However, demyelinated explants that are
continuously exposed to myelin-specific MS rAb fail to activate microglia, and oligodendrocyte maturation is
inhibited. Similarly, targeted depletion of microglia following rAb-mediated demyelination blocks
oligodendrocyte maturation preventing active remyelination. Using single cell RNASeq (scRNASeq) on
microglia isolated from remyelinating explants, we identified transcriptionally distinct microglial subsets that are
associated with successful or failed remyelination. Hence, we hypothesize that microglial signals are critical
for oligodendrocyte responses during the transition from early myelinating to actively myelinating
oligodendrocyte, and myelin-specific MS autoantibody modulates these signals to arrest remyelination. To test
our hypothesis, we propose three complementary specific aims. In Aim 1, we will evaluate microglial and
oligodendrocyte responses in in vivo models of MS rAb-mediated demyelination and compare those responses
to those seen in toxin-mediated demyelination. Intrathalamic or corpus callosum injection of myelin-specific MS
rAb plus HC will be performed in conjunction with pharmacologic microglial depletion and chronic
administration of MS rAb to validate the impact of microglial responses on remyelination in the intact nervous
system. Comparable studies will be done following lysolecithin-induced demyelination, which has a very
different time course of microglial activation and remyelination. In Aim 2, we will study the dynamics of
demyelination, microglial responses and oligodendrocyte regeneration in situ using intravital imaging following
cortical demyelination. This real-time analysis of myelin loss, microglial activation and remyelination will be
compared to that seen following cuprizone-mediated demyelination. Finally, in Aim 3, we will investigate the
mechanisms by which microglia impact remyelination using ex vivo cerebellar slices demyelinated with myelin-
specific rAb plus human complement (HC). We will focus on investigating the role of several microglial genes
identified by scRNASeq that are expected to promote or impair remyelination. Normal appearing white matt...

## Key facts

- **NIH application ID:** 10073272
- **Project number:** 1R01NS115488-01A1
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Jeffrey L Bennett
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $483,565
- **Award type:** 1
- **Project period:** 2020-06-15 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10073272

## Citation

> US National Institutes of Health, RePORTER application 10073272, Microglial impact on remyelination (1R01NS115488-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10073272. Licensed CC0.

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