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

肿瘤易感基因 101，一种新的小胶质细胞疗法候选药物，用于治疗阿尔茨海默病，可预防认知能力下降

基本信息

批准号：
10710931
负责人：
Seiko Ikezu
金额：
$ 199.42万
依托单位：
MAYO CLINIC JACKSONVILLE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2026-08-31
项目状态：
未结题

项目摘要

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.

项目摘要/摘要迫切需要开发治疗阿尔茨海默氏病（AD），预计会影响139 到2050年，世界上有百万人。新兴的证据表明，脑部先天免疫细胞，小胶质细胞，在神经退行性的过程中，他们在清除中扮演重要角色，与神经退行性的进展有关聚集的蛋白质，例如淀粉样蛋白β斑块或磷酸化的tau（p-tau）。我们最近发现了含有p-tau的细胞外蔬菜（EV）介导的AD中tau传播的机制在App Ki小鼠模型中从斑块相关的小胶质细胞中分泌。在此应用程序中，我们旨在定位肿瘤敏感性基因101，TSG101，运输所需的内体分选络合物之一（ESCRT）-i，批判性地调节小胶质细胞中的EV合成以操纵EV分泌并减轻tau病理学 PS19 tauopathy小鼠的发育。我们令人兴奋的初步数据表明，有条件地敲门在PS19 tauopathy小鼠中，将小胶质细胞TSG101显着改善了7个月大时的认知功能，减少了tau病理，并防止了海马场的突触损失。此外，RNA海马组织大块RNA序列结果表明，消融小胶质TSG101降低了海马神经炎症，补体途径和小胶质细胞神经退行性表型特征基因，表明小胶质细胞TSG101与免疫调节至关重要。我们将验证我们的初步结果，并进一步研究TSG101在小胶质激活和/或具有三个实验范式的AD病理学。 i）针对AD动物模型小胶质细胞中的TSG101，II）在体外小胶质细胞中靶向tsg101，靶向在AD动物中重构的人类小胶质细胞中的TSG101 体内模型。这项研究的成功完成将验证TSG101作为一个新型的治疗靶标小胶质细胞抑制其EV分泌，Tau传播和突触修剪通过完成途径并提供基本知识，以将小胶质细胞分子作为AD疗法。