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

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.