White matter aging drives microglial diversity

• DOI: 10.1016/j.neuron.2021.01.027
• Publication Date: 2021-02-19T04:54:50Z
• Authors: Shima Safaiyan; Simon Besson-Girard; Tuğberk Kaya; Ludovico Cantuti-...; Lu Liu; Hao Ji; Martina Schifferer; Garyfallia Gouna; Fumere Usifo; Nirmal Kannaiyan; Dirk Fitzner; Xianyuan Xiang; Moritz J. Rossner; Matthias Brendel; Ozgun Gokce; Mikael Simons
• Keywords: TREM2; Apolipoprotein E

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.