Human early-onset dementia caused by DAP12 deficiency reveals a unique signature of dysregulated microglia

Nat Immunol. 2023 Mar;24(3):545-557. doi: 10.1038/s41590-022-01403-y. Epub 2023 Jan 19.


The TREM2-DAP12 receptor complex sustains microglia functions. Heterozygous hypofunctional TREM2 variants impair microglia, accelerating late-onset Alzheimer's disease. Homozygous inactivating variants of TREM2 or TYROBP-encoding DAP12 cause Nasu-Hakola disease (NHD), an early-onset dementia characterized by cerebral atrophy, myelin loss and gliosis. Mechanisms underpinning NHD are unknown. Here, single-nucleus RNA-sequencing analysis of brain specimens from DAP12-deficient NHD individuals revealed a unique microglia signature indicating heightened RUNX1, STAT3 and transforming growth factor-β signaling pathways that mediate repair responses to injuries. This profile correlated with a wound healing signature in astrocytes and impaired myelination in oligodendrocytes, while pericyte profiles indicated vascular abnormalities. Conversely, single-nuclei signatures in mice lacking DAP12 signaling reflected very mild microglial defects that did not recapitulate NHD. We envision that DAP12 signaling in microglia attenuates wound healing pathways that, if left unchecked, interfere with microglial physiological functions, causing pathology in human. The identification of a dysregulated NHD microglia signature sparks potential therapeutic strategies aimed at resetting microglia signaling pathways.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Brain / metabolism
  • Dementia* / metabolism
  • Dementia* / pathology
  • Humans
  • Membrane Glycoproteins / metabolism
  • Mice
  • Microglia / metabolism
  • Receptors, Immunologic / metabolism
  • Subacute Sclerosing Panencephalitis* / metabolism
  • Subacute Sclerosing Panencephalitis* / pathology


  • Membrane Glycoproteins
  • Receptors, Immunologic
  • Trem2 protein, mouse
  • TYROBP protein, human

Supplementary concepts

  • Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy