White matter aging drives microglial diversity

Neuron. 2021 Apr 7;109(7):1100-1117.e10. doi: 10.1016/j.neuron.2021.01.027. Epub 2021 Feb 18.


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.

Keywords: ApoE; Trem2; microglia, aging; myelin; white matter.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / physiology
  • Alzheimer Disease / genetics
  • Animals
  • Apolipoproteins E / genetics
  • Demyelinating Diseases / pathology
  • Gene Expression Regulation
  • Gray Matter / cytology
  • Gray Matter / growth & development
  • Immunohistochemistry
  • Membrane Glycoproteins / biosynthesis
  • Membrane Glycoproteins / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microglia / physiology*
  • Microglia / ultrastructure
  • Myelin Sheath / metabolism
  • Receptors, Immunologic / biosynthesis
  • Receptors, Immunologic / genetics
  • Sequence Analysis, RNA
  • Signal Transduction / physiology
  • Single-Cell Analysis
  • White Matter / cytology*
  • White Matter / growth & development*


  • Apolipoproteins E
  • Membrane Glycoproteins
  • Receptors, Immunologic
  • Trem2 protein, mouse