DAP12-deficient microglia adopt a TREM2-independent antigen-presenting state with a glial-to-neuronal cascade in Nasu-Hakola disease

Nasu-Hakola disease, a rare dementia affecting around 200 individuals globally, is caused by mutations in TYROBP, which encodes DAP12, or its receptor TREM2. Microglia, the immune cells of the brain, can transform from a surveillant state to a reactive state when DAP12-deficient. This transformation, however, remains unclear. Researchers have now analyzed prefrontal cortex and hippocampus tissue samples from an NHD patient and healthy controls using single-nucleus RNA sequencing and spatial transcriptomics to understand the cellular changes in the brain.

The study found that NHD microglia adopted an antigen-presenting state driven by CIITA, a gene involved in Major Histocompatibility Complex class II expression, without the involvement of TREM2. This state was characterized by the upregulation of complement, iron, glycolysis, and Fc receptor genes. Notably, astrocytes became pan-reactive, losing metallothionein expression, oligodendrocytes exhibited a loss of mature cells and cholesterol synthesis, and excitatory neurons lost their presynaptic and activity programs.

These changes were consistent across different brain regions and supported by a larger cohort of patients. The findings suggest that DAP12 deficiency leaves microglia in an antigen-presenting state, but not as advanced as the TREM2-dependent state, and initiates a glial-to-neuronal cascade throughout the brain.