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.

项目摘要/摘要 人们迫切需要开发治疗阿尔茨海默病(AD)的方法，据预测，阿尔茨海默病将影响139人 到2050年，世界人口将达到100万。新出现的证据表明，大脑的先天免疫细胞、小胶质细胞、 在神经退行性变的进程中起关键作用，同时它们在清除 聚集蛋白，如淀粉样蛋白β斑块或磷酸化tau(p-tau)。我们最近发现了 含p-tau的细胞外小泡增多介导的tau在AD中的增殖机制 由APPKI小鼠模型斑块相关小胶质细胞分泌。在此应用程序中，我们的目标是 肿瘤易感基因101，Tsg101，运输所需的内体分选复合体(ESCRT)-I， 关键调控小胶质细胞EV合成，调控EV分泌，减轻tau病理 多发性硬化症小鼠的研制。我们令人兴奋的初步数据表明，有条件地敲门 在PS19自闭症小鼠中，Out小胶质细胞TSG101显著改善了7个月大的认知功能， 减少tau病理，防止海马区突触丢失。此外，RNA海马区 组织块状RNA序列结果表明，消融小胶质细胞Tsg101使海马区减少 神经炎症、补体途径和小胶质细胞退变表型特征基因， 提示小胶质细胞Tsg101在免疫调节中起重要作用。 我们将验证我们的初步结果，并进一步研究Tsg101在小胶质细胞激活和/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Tsg101，ii) 在人小胶质细胞中靶向TSG101 III)在AD动物体内重组的人小胶质细胞中靶向TSG101 活体模型。这项研究的成功完成将验证Tsg101作为一种新的治疗靶点 小胶质细胞通过补体抑制EV分泌、tau增殖和突触修剪 并为靶向小胶质分子作为阿尔茨海默病的治疗药物提供基础知识。