Tumor susceptibility gene 101, a new microglial therapy candidate for Alzheimer’s disease to prevent cognitive decline

PROJECT SUMMARY/ABSTRACT There is an urgent need for developing the cure for Alzheimer’s disease (AD), which is predicted to affect 139 million people in the world by 2050. Emerging evidence have shown that brain innate immune cells, microglia, are critically involved in the progression of neurodegeneration while they take important roles in clearing aggregated protein such as amyloid β plaque or phosphorylated tau(p-tau). We have recently uncovered the mechanism of tau propagation in AD mediated by increased extracellular vesicles (EVs) containing p-tau secreted from plaque associated microglia in APP KI mouse model. In this application, we aimed for targeting tumor susceptibility gene 101, Tsg101, one of endosomal sorting complexes required for transport (ESCRT)-I, critically regulating the EV synthesis in microglia to manipulate EV secretion and mitigate tau pathology development in PS19 tauopathy mouse. Our exciting preliminary data have shown that conditionally knocking out microglial TSG101 in PS19 tauopathy mice significantly improved cognitive functions at 7 months of age, reduced tau pathology and prevented synaptic loss in the hippocampal field. Furthermore, RNA hippocampal tissue bulk RNA sequence results indicated that ablating microglial Tsg101 reduced hippocampal neuroinflammation, complement pathway and microglial neurodegenerative phenotype signature genes, suggesting that microglial Tsg101 is critically involved in immune regulation. We will validate our preliminary results and further investigate the role of Tsg101 on microglial activation and/or AD pathology with three experimental paradigms. i) targeting Tsg101 in microglia of AD animal models, ii) targeting TSG101 in human microglia in vitro iii) targeting TSG101 in human microglia reconstituted in AD animal models in vivo. The successful completion of this study will validate Tsg101 as a novel therapeutic target of microglia for the suppression of their EV secretion, tau propagation and synaptic pruning via complement pathway and give fundamental knowledge for targeting microglial molecules as AD therapeutics.