Alzheimer’s disease-linked risk alleles elevate microglial cGAS-associated senescence and neurodegeneration in a tauopathy model

Abstract

SUMMARYThe strongest risk factors for Alzheimer’s disease (AD) include the χ4 allele of apolipoprotein E (APOE), theR47Hvariant of triggering receptor expressed on myeloid cells 2 (TREM2), and female sex. Here, we combineAPOE4andTREM2R47H(R47H) in femaleP301Stauopathy mice to identify the pathways activated when AD risk is the strongest, thereby highlighting disease-causing mechanisms. We find that theR47Hvariant induces neurodegeneration in femaleAPOE4mice without impacting hippocampal tau load. The combination ofAPOE4andR47Hamplified 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-R47Hmicroglia 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.