DAP12-deficient microglia adopt a TREM2-independent antigen-presenting state with a glial-to-neuronal cascade in Nasu-Hakola disease
Leon, J.; Yoshinaga, S.; Koya, I.; Palafox, G.; Ando, Y.; Kubo, K.-i.; Moody, J.; Takao, M.; Carninci, P.; Shin, J.; Condello, C.; Okano, H.; Hon, C. C.; Morimoto, S.
Show abstract
Nasu-Hakola disease (NHD), a dementia with about 200 cases worldwide, is caused by loss-of-function mutation of TYROBP, encoding DAP12, or its receptor TREM2. TREM2-DAP12 is the switch that converts microglia from a surveillant to a reactive state; what DAP12-deficient microglia become and to what extent they reshape their microenvironment is unknown. We profiled prefrontal cortex and hippocampus from an NHD donor and control by single-nucleus RNA sequencing and mapped the glial changes in situ by spatial transcriptomics. NHD microglia adopted a CIITA-driven, MHC class II-high antigen-presenting state with complement, iron and glycolytic programs and Fc receptors but not the TREM2-dependent lipid program. Astrocytes became pan-reactive and lost metallothionein expression, oligodendrocytes lost mature cells and cholesterol synthesis, and excitatory neurons lost presynaptic and activity programs, consistently between regions and across a published cohort. DAP12 deficiency left microglia in an antigen-presenting state short of the TREM2-dependent arm, accompanied by a glial-to-neuronal cascade.
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