White matter aging drives microglial diversity

Aging results in gray and white matter degeneration, but the specific microglial responses are unknown. Using single-cell RNA sequencing from white and gray matter separately, we identified white matter-associated microglia (WAMs), which share parts of the disease-associated microglia (DAM) gene signature and are characterized by activation of genes implicated in phagocytic activity and lipid metabolism. WAMs depend on triggering receptor expressed on myeloid cells 2 (TREM2) signaling and are aging dependent. In the aged brain, WAMs form independent of apolipoprotein E (APOE), in contrast to mouse models of Alzheimer’s disease, in which microglia with the WAM gene signature are generated prematurely and in an APOE-dependent pathway similar to DAMs. Within the white matter, microglia frequently cluster in nodules, where they are engaged in clearing degenerated myelin. Thus, WAMs may represent a potentially protective response required to clear degenerated myelin accumulating during white matter aging and disease. [Display omitted] •scRNA-seq identifies age-dependent white matter-associated microglia (WAMs)•WAMs form nodules that are engaged in clearing degenerated myelin•WAM formation depends on TREM2 but not on APOE signaling•In mouse models of Alzheimer’s disease, the WAM response occurs before DAM Safaiyan et al. identify white matter-associated microglia (WAMs), which form in a TREM2-dependent but APOE-independent manner in aging white matter, where they form nodules that are engaged in phagocytosing damaged myelin. Thus, WAMs represents a response required to clear degenerated myelin that accumulates during white matter aging and disease.