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; Aging; metabolism [Myelin Sheath]; genetics [Alzheimer Disease]; biosynthesis [Membrane Glycoproteins]; growth & development [White Matter]; Mice; 03 medical and health sciences; Trem2 protein, mouse; Apolipoproteins E; genetics [Membrane Glycoproteins]; Alzheimer Disease; physiology [Signal Transduction]; genetics [Receptors, Immunologic]; Animals; ddc:610; Gray Matter; Receptors, Immunologic; microglia, aging; Myelin Sheath; Mice, Knockout; 0303 health sciences; Membrane Glycoproteins; cytology [White Matter]; Sequence Analysis, RNA; growth & development [Gray Matter]; cytology [Gray Matter]; physiology [Aging]; Immunohistochemistry; White Matter; physiology [Microglia]; Mice, Inbred C57BL; ultrastructure [Microglia]; biosynthesis [Receptors, Immunologic]; myelin; Gene Expression Regulation; genetics [Apolipoproteins E]; Microglia; Single-Cell Analysis; pathology [Demyelinating Diseases]; white matter; ApoE; Demyelinating Diseases; Signal Transduction

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.