Astrocytic Sox9 preserves cognitive function in models of Alsheimer's Disease [RNA-Seq]

Astrocytes play essential roles in the brain and their dysfunction is associated with nearly every form of neurological disease. Despite their ubiquity, our knowledge of how astrocytes contribute to disease pathogenesis is incomplete, accordingly harnessing their biology towards therapeutics remains a major challenge. Here we show that the transcription factor Sox9 plays a context specific role in maintaining astrocyte function and circuit activity in the aging hippocampus and Alzheimer's Disease (AD) models. We found that Sox9 overexpression in astrocytes in AD models clears existing amyloid beta (Aß) plaques and preserves cognitive function. Mechanistically, Sox9 promotes the phagocytosis of Aß plaques by astrocytes through the regulation of the phagocytic receptor MEGF10, which is sufficient to preserve cognitive function in AD models. Collectively, these studies highlight new roles for astrocytic Sox9 during aging and AD, while identifying Sox9-MEGF10 signaling as a prospective astrocyte-based therapeutic approach to ameliorate cognitive decline in neurodegenerative disease. Overall design: RNA-Seq profiling of young (4months) and aged (18months) astrocytes sorted from the hippocampus using GFP expression in Aldh1l1-GFP mice. RNA-Seq profiling of wildtype and their Sox9 knockout age matched counterparts in young (4months) and aged (18months) astrocytes sorted from the hippocampus using GFP expression in Aldh1l1-GFP;Sox9fl/fl mice. RNA-Seq profiling of astrocytes sorted from the hippocampus in mice modeling alzheimer's disease (AD) with and without overexpression of Sox9.