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.

Prophylactic effect of chronic immunosuppression in a mouse model of CSF-1 receptor-related leukoencephalopathy.

Mutations leading to colony-stimulating factor-1 receptor (CSF-1R) loss-of-function or haploinsufficiency cause CSF1R-related leukoencephalopathy (CRL), an adult-onset disease characterized by loss of myelin and neurodegeneration, for which there is no effective therapy. Symptom onset usually occurs in the fourth decade of life and the penetrance of disease in carriers is high. However, familial studies have identified a few carriers of pathogenic CSF1R mutations that remain asymptomatic even in their seventh decade of life, raising the possibility that the development and severity of disease might be influenced by environmental factors. Here we report new cases in which long-term glucocorticoid treatment is associated with asymptomatic status in elder carriers of pathogenic CSF-1R mutations. The main objective of the present study was to investigate the link between chronic immunosuppression initiated pre-symptomatically and resistance to the development of symptomatic CRL, in the Csf1r+/- mouse model. We show that chronic prednisone administration prevents the development of memory, motor coordination and social interaction deficits, as well as the demyelination, neurodegeneration and microgliosis associated with these deficits. These findings are in agreement with the preliminary clinical observations and support the concept that pre-symptomatic immunosuppression is protective in patients carrying pathogenic CSF1R variants associated with CRL. Proteomic analysis of microglia and oligodendrocytes indicates that prednisone suppresses processes involved in microglial activation and alleviates senescence and improves fitness of oligodendrocytes. This analysis also identifies new potential targets for therapeutic intervention.