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

Area of Science:

• Neuroscience
• Genetics
• Cell Biology

Background:

• The TREM2-DAP12 receptor complex is crucial for microglial function.
• Defects in TREM2 or DAP12 cause Nasu-Hakola disease (NHD), an early-onset dementia.
• The precise mechanisms driving NHD pathology remain unclear.

Purpose of the Study:

• To investigate the molecular mechanisms underlying Nasu-Hakola disease (NHD) by analyzing brain tissue from affected individuals.
• To identify specific cellular signatures and signaling pathway dysregulations in NHD.

Main Methods:

• Single-nucleus RNA-sequencing (snRNA-seq) was performed on brain specimens from individuals with DAP12-deficient NHD.
• Comparative analysis of human NHD data with mouse models lacking DAP12 signaling.

Main Results:

• A distinct microglia signature in NHD patients showed elevated RUNX1, STAT3, and TGF-β signaling, indicative of heightened repair responses.
• This signature correlated with astrocyte wound healing profiles and oligodendrocyte myelination defects.
• Pericyte profiles suggested associated vascular abnormalities.
• Mouse models with DAP12 deficiency did not fully recapitulate the NHD phenotype.

Conclusions:

• DAP12 signaling in microglia normally suppresses wound healing pathways, preventing interference with physiological functions.
• Dysregulation of these pathways in NHD, particularly in microglia, contributes to the observed pathology.
• The identified NHD microglia signature offers potential therapeutic targets for resetting cellular signaling pathways in dementia.