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White matter aging drives microglial diversity

Authors: Safaiyan, Shima; Besson-Girard, Simon; Kaya, Tuğberk; Cantuti-Castelvetri, Ludovico; Liu, Lu; Ji, Hao; Schifferer, Martina; Gouna, Garyfallia; Usifo, Fumere; Kannaiyan, Nirmal; Fitzner, Dirk; Xiang, Xianyuan; Rossner, Moritz J.; Brendel, Matthias; Gokce, Ozgun; Simons, Mikael

Online: https://www.sciencedirect.com/science/article/pii/S0896627321000738

Issue: Neuron . 2021 Apr 7;109(7):1100-1117.e10.


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.