Single cell genomic and epigenomic analysis of mouse and human Alzheimer's Disease

We profiled the genomic and epigenomic landscapes using 10x multiome of nuclei from the dorsal hippocampus of male and female 5xFAD AD mice and wild-type controls at 3, 9, and 18 months of age. Our analysis revealed increased disease-associated and interferon-related cell states in microglia with aging and AD, with more pronounced changes in female AD mice. The cGAS-STING pathway was upregulated in microglia of aged 5xFAD mice. Pharmacological inhibition of STING with H-151 reduced amyloid beta plaques in the hippocampus and mitigated spatial memory decline in aged 5xFAD mice. We also generated 10x multiome data from 5xFAD mice treated with the STING inhibitor H-151, which shifted microglia from an interferon-related state to a neuroprotective state with enhanced amyloid beta clearance. We identified Mef2 binding sites enriched in the enhancers of amyloid beta clearance genes, and a deep learning model revealed an increased contribution of these Mef2 sites to enhancer activity following STING inhibition. Additionally, we generated 10x multiome profiles from the hippocampus of human AD patients, observing increased cGAS-STING effector IRF3 activity and reduced MEF2 activity in AD microglia compared to neurotypical and high-pathology controls.