Alzheimer's disease-linked risk alleles elevate microglial cGAS-associated senescence and neurodegeneration in a tauopathy model [snRNAseq]
The strongest risk factors for Alzheimer's disease (AD) include the ?4 allele of apolipoprotein E (APOE), the R47H variant of triggering receptor expressed on myeloid cells 2 (TREM2), and female sex. Here, we combine APOE4 and TREM2R47H (R47H) in female P301S tauopathy mice to identify the pathways activated when AD risk is the strongest, thereby highlighting disease-causing mechanisms. We find that the R47H variant induces neurodegeneration in female APOE4 mice without impacting hippocampal tau load. The combination of APOE4 and R47H amplified tauopathy-induced cell-autonomous microglial cGAS-STING signaling and type-I interferon response, and interferon signaling converged across glial cell types in the hippocampus. APOE4-R47H microglia displayed cGAS- and BAX-dependent upregulation of senescence, showing association between neurotoxic signatures and implicating mitochondrial permeabilization in pathogenesis. By uncovering pathways enhanced by the strongest AD risk factors, our study points to cGAS-STING signaling and associated microglial senescence as potential drivers of AD risk. Overall design: Droplet-based single nuclear RNA sequencing of hippocampus from a) female mice with APOE3_NTG_TREM2-WT (n=3), APOE3_P301S_TREM2-WT (n=3), APOE3_P301S_TREM2-R47H (n=3), APOE4_NTG_TREM2-WT (n=3), APOE4_P301S_TREM2-WT (n=3), APOE4_P301S_TREM2-R47H (n=3); b) male mice with APOE4_NTG_TREM2-WT (n=3), APOE4_P301S_TREM2-WT (n=3), APOE4_P301S_TREM2-R47H (n=3).