Washington University
Neurology

Author Of 1 Presentation

Neuroprotection, Regeneration and/or Remyelination Late Breaking Abstracts

LB1265 - "TREM2 activation on microglia promotes myelin debris clearance and remyelination in a model of CNS demyelination." (ID 2163)

Speakers
Presentation Number
LB1265
Presentation Topic
Neuroprotection, Regeneration and/or Remyelination

Abstract

Background

Multiple sclerosis (MS) is an inflammatory, demyelinating and neurodegenerative disease of the central nervous system (CNS). In MS, impaired generation of mature oligodendrocytes (OLs) from oligodendrocyte precursor cells (OPCs) leads to persistent demyelination, myelin debris accumulation and axonal damage. Efficient myelin debris removal and clearance by phagocytic cells, such as microglia in the brain, are critical to eliminating inhibitory signals interfering with OPC activation and recruitment. An important modulator of microglia functions is the triggering receptor expressed on myeloid cells-2 (TREM2), an innate immune receptor that promotes microglial survival, proliferation and phagocytic activity. Homozygous loss-of-function mutations in TREM2 genes cause Nasu–Hakola disease (NHD). In the context of mouse models of MS, it has been previously demonstrated that mice lacking TREM2 have a striking defect in microglia activation and myelin debris clearance in the cuprizone (CPZ) model and that intravenous injection of TREM2-transduced myeloid cells is beneficial in experimental autoimmune encephalomyelitis (EAE).

Objectives

The goal of this project is to explore the effect of antibody-mediated TREM2 activation on microglia in the CPZ model of demyelination of the CNS.

Methods

Studies on human post-mortem CNS tissues (8 subjectes with MS and 4 non-MS) were performed on 20 fresh-frozen brain and spinal cord tissues. Trem2+/− mice were fed a 0.2% Bis-(cyclohexanone) oxaldihydrazone (cuprizone) diet for 4 weeks or for 4 weeks followed by 3 days, 7 days, or 14 days on regular chow. Remyelination and axonal integrity were analyzed by transmission electron microscopy, qPCR for myelin transcripts and neurofilament light detection in serum. We analyzed the gene expression profile (Affymetrix HuGene-1_0-st-v1 Microarrays) of macrophages obtained from the peripheral blood of three patients affected by NHD and healthy controls.

Results

We demonstrated that TREM2 was highly expressed on myelin-laden phagocytes in active demyelinating lesions in the CNS of subjects with MS. In gene expression studies, macrophages from subjects affected by Nasu-Hakola (lacking TREM2) displayed a defect in phagocytic pathways. Treatment of Trem2+/− mice with a new TREM2 agonistic antibody promoted the clearance of myelin debris in the cuprizone model of CNS demyelination. Effects included enhancement of myelin uptake and degradation, resulting in accelerated myelin debris removal by microglia. Most importantly, antibody-dependent TREM2 activation on microglia increased density of oligodendrocyte precursors in areas of demyelination, as well as the formation of mature oligodendrocytes thus enhancing remyelination and axonal integrity.

Conclusions

These results are extremely relevant as they propose TREM2 on microglia as a potential new strategy to promote remyelination.

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