White matter aging drives microglial diversity

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
DOI: 10.1016/j.neuron.2021.01.027 Publication Date: 2021-02-19T04:54:50Z
ABSTRACT
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.
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