Journal Article

Trem2 Enhances Demyelination in the Csf1r+/− Mouse Model of Leukoencephalopathy

Chitu, Violeta, Biundo, Fabrizio, Oppong-Asare, Jude, Gökhan, Şölen, Stanley, E. Richard, Chen, Edward

2023

Overview

Colony-stimulating factor-1 receptor (CSF-1R)-related leukoencephalopathy (CRL) is a neurodegenerative disease that triggers early demyelination, leading to an adult-onset dementia. Triggering receptor expressed on myeloid cells-2 (TREM2) is a microglial receptor that promotes the activation of microglia and phagocytic clearance of apoptotic neurons and myelin debris. We investigated the role of Trem2 in the demyelination observed in the Csf1r+/− mouse model of CRL. We show that elevation of Trem2 expression and callosal demyelination occur in 4–5-month-old Csf1r+/− mice, prior to the development of symptoms. Absence of Trem2 in the Csf1r+/− mouse attenuated myelin pathology and normalized microglial densities and morphology in the corpus callosum. Trem2 absence also prevented axonal degeneration and the loss of cortical layer V neurons observed in Csf1r+/− mice. Furthermore, the absence of Trem2 prevented the accumulation of myelin-derived lipids in Csf1r+/− macrophages and reduced the production of TNF-α after myelin engulfment. These data suggest that TREM2 contributes to microglial dyshomeostasis in CRL.

• Publisher: MDPI AG,MDPI
• Subject: Adapter proteins / ALSP / Antibodies / Apoptosis / Brain / Cerebrospinal fluid / Colony-stimulating factor / Corpus callosum / CSF-1 receptor / Dementia disorders / Demyelination / Genotype & phenotype / HDLS / Kinases / Leukoencephalopathy / Lipids / Macrophage colony-stimulating factor / Macrophages / Microglia / Mutation / Myelin / Myeloid cells / Neurodegeneration / Neurodegenerative diseases / Oxidative stress / Pathology / Phagocytes / TREM2 / Tumor necrosis factor-α