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

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/10710931
• 关键词: Ablation; Affect; Age Months; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease therapeutic; Alzheimer' s disease therapy; Amyloid; Amyloid beta-Protein; Animal Disease Models; Animal Model; Biogenesis; Brain; Cell Line; Cells; Clustered Regularly Interspaced Short Palindromic Repeats; Collaborations; Complex; Corn Oil; Data; Development; Down-Regulation; Endosomes; Evaluation; Fire - disasters; Gene Targeting; Generations; Glioma; Gliosis; Goals; Hippocampus; Human; Immune; Impaired cognition; Implant; In Vitro; Knock-in Mouse; Knowledge; Mediating; Memory; Microglia; Modeling; Molecular; Monitor; Mus; Nerve Degeneration; Parahippocampal Gyrus; Pathogenicity; Pathologic; Pathology; Persons; Phagocytosis; Phenotype; Play; Probability; RNA; RNA Sequences; Reporter Genes; Research Personnel; Role; Saline; Senile Plaques; Sonication; Sorting; Synapses; TSG101 gene; Tamoxifen; Tauopathies; Tissues; Treatment Efficacy; Work; aged; amyloid pathology; brain tissue; cerebral atrophy; cognitive function; comparison control; complement pathway; conditional knockout; dentate gyrus; entorhinal cortex; extracellular vesicles; genetic signature; glial activation; human disease; immunoregulation; implantation; improved; in vivo; in vivo Model; induced pluripotent stem cell; invention; male; mouse model; neurodegenerative phenotype; neuroinflammation; neuropathology; new therapeutic target; novel; prevent; protein aggregation; reconstitution; single-cell RNA sequencing; synaptic pruning; targeted treatment; tau Proteins; tau aggregation; tau-1; transcriptomics

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.

项目总结/摘要 目前迫切需要开发治疗阿尔茨海默病（AD）的方法，预计该疾病将影响139 到2050年，世界上将有100万人。新出现的证据表明，大脑先天免疫细胞，小胶质细胞， 在神经退行性疾病的发展中起着重要作用， 聚集的蛋白质，如淀粉样蛋白β斑块或磷酸化tau（p-tau）。我们最近发现， AD中由含有p-tau的细胞外囊泡（EV）增加介导的tau传播机制 在APP KI小鼠模型中从斑块相关的小胶质细胞分泌。在这个应用程序中，我们的目标是 肿瘤易感基因101，Tsg 101，转运所需的内体分选复合物之一（ESCRT）-I， 严格调节小胶质细胞中的EV合成以操纵EV分泌并减轻tau病理 在PS19 tau蛋白病小鼠中的发育。我们令人兴奋的初步数据表明， PS19 tau蛋白病小鼠中的小胶质细胞TSG 101显著改善了7月龄时的认知功能， 减少了海马区的tau病理学并防止了突触丢失。此外，RNA海马 组织整体RNA测序结果表明，切除小胶质细胞Tsg 101减少了海马 神经炎症、补体途径和小胶质细胞神经变性表型标记基因， 提示小胶质细胞Tsg 101在免疫调节中起关键作用。 我们将验证我们的初步结果，并进一步研究Tsg 101对小胶质细胞激活和/或 AD病理学与三种实验范式。i）靶向AD动物模型小胶质细胞中的Tsg 101，ii） iii）靶向在AD动物中重构的人小胶质细胞中的TSG 101 体内模型。这项研究的成功完成将验证Tsg 101作为一种新的治疗靶点， 小胶质细胞通过补体抑制其EV分泌、tau传播和突触修剪 通路，并为靶向小胶质细胞分子作为AD治疗剂提供基础知识。