Demyelination and ensuing axonal damage are hallmarks of numerous neurodegenerative disorders. Novel treatment strategies seek to enhance remyelination and axonal recovery through acceleration of myelin debris clearance by phagocytic microglia. TREM2 is a receptor expressed by microglia that has been implicated in the regulation of phagocytosis, migration and anti-inflammatory activity. Here, we further elucidated the role of TREM2 in de- and remyelination processes by means of multiparametric in vivo MRI. We combined a TREM2 loss-of-function mouse model with cuprizone feeding as an accepted model for demyelination. Deficiency of TREM2 leads to progressive structural disintegration and absence of proper remyelination.