Role of a novel risk loci HAVCR2 of late-onset Alzheimer's disease in the regulation of microglial response in neurodegeneration

迟发性阿尔茨海默病的新风险位点 HAVCR2 在调节神经退行性小胶质细胞反应中的作用

• 批准号: 10608400
• 负责人: Oleg Butovsky
• 金额: $ 83.13万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10608400
• 关键词: Affect; Agonist; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid beta-Protein Precursor; Animal Model; Antibodies; Antigen Presentation; Antigens; Area; Autoimmune Diseases; Basic Science; Behavior; Binding; Blocking Antibodies; Brain; Cell physiology; Chronic; Cognitive; Data; Dementia; Dendritic Cells; Deposition; Development; Disease; Disease Progression; Disease associated microglia; Genetic; Goals; Human; Immunity; Investigation; Laboratories; Late Onset Alzheimer Disease; Ligands; Link; Maintenance; Malignant Neoplasms; Microglia; Modeling; Mus; Myeloid Cell Activation; Myeloid Cells; Natural Immunity; Nerve Degeneration; Neurodegenerative Disorders; Onset of illness; Outcome; Pathology; Phagocytes; Phagocytosis; Phenotype; Phosphorylation; Play; Receptor Signaling; Regulation; Role; Signal Induction; Signal Transduction; T-Lymphocyte; TGFB1 gene; Tauopathies; Transcript; Translating; Tumor Immunity; Viral Cancer; Virus Diseases; Work; aging brain; cancer clinical trial; cancer therapy; cytokine; drug candidate; exhaustion; genetic linkage; genetic risk factor; genome wide association study; glial activation; immunoregulation; improved; induced pluripotent stem cell; mouse model; neuroinflammation; novel; novel therapeutic intervention; pharmacologic; response; restraint; risk variant; synergism; therapy development

PROJECT SUMMARY Recent largest GWAS identified HAVCR2 (TIM3) genetic risk factor for late-onset Alzheimer’s disease (LOAD). Our laboratory discovered and cloned Tim3 as an inhibitory molecule that induces T cell exhaustion in cancer1. Blocking antibodies to Tim3 are being approved for the treatment of cancer. However, we have now identified that Tim3 is not only expressed on T cells, but also on myeloid cells and dendritic cells, where TIM3 restrains dendritic cell function and regulate anti-tumor immunity2. In the CNS, HAVCR2 was identified as one of the top 100 enriched transcripts and is specifically expressed in both mouse and human microglia3-5, but its role and function in microglia is unknown. Our long-term goal is to define the role of TIM3 in regulation of microglia in neurodegeneration. We made the following observations: 1) Tim3 inhibits microglial activation and phagocytosis: deletion of Tim3 in dendritic cells boosted antigen presentation and we find that TIM3 also regulates microglial activation and phagocytosis; 2) TGFb-Tim3 axis regulates microglia phenotype switch in neurodegeneration: we find that TGFb is the key driver for the induction of Tim3 and once expressed it synergizes with TGFBR to potentiate TGFB signaling, loss of Tim3 switches M0-homeostatic microglia to an MGnD-nondegenerative phenotype; and 3) TIM3 deletion in microglia reduces plaque burden in 5xFAD mice. These data support the genetic linkage studies and show the importance of Tim3 in regulating disease pathology in AD by modulating microglial function. Based on these studies, we hypothesize that TIM3 is a key regulatory molecule in microglia that inhibits their response to neurodegeneration, migratory and phagocytic functions and thereby inhibit plaque clearance resulting in promotion of Ab deposition, development, and progression of AD in aging brain. Based on this hypothesis we have proposed three aims: Aim 1: Define how TIM3 regulates phenotype and functions in 5xFAD and P301S mouse AD models. We propose to study the effect of microglial deletion of Tim3 in neurodegeneration and brain tauopathy using the mouse models of AD. Aim 2: What is the role of TGFb signaling in the regulation of Tim3 expression and function in microglia and development of AD? Since TGFb plays a critical role in maintenance of the homeostatic phenotype in microglia, we propose to study how TGFb signaling induces Tim3 expression and promotes homeostatic behavior of microglia by cooperating with TGFb receptor signaling. Aim 3: Define the role of TIM3 in the regulation of human microglial function in AD. Determine how TIM3 impacts human iPSC-derived microglia activation and functions. We will examine whether genetic or pharmacologic inhibition of TIM3 has a similar effect on iPSCs-derived human microglia expressing the MGnD phenotype by utilizing a humanized chimeric mouse model of AD for treatment with human anti-Tim3 antibody IN SUMMARY, targeting TIM3 in microglia may provide a novel approach for therapeutic modulation of innate immunity in AD and dementia.

项目摘要 最近最大的GWAS确定了晚期发病的阿尔茨海默氏病（负载）的HAVCR2（TIM3）遗传危险因素。 我们的实验室发现并克隆Tim3是一种抑制性分子，可在癌症中诱导T细胞疲劳1。 阻塞TIM3的抗体已被批准用于治疗癌症。但是，我们现在已经确定了 该TIM3不仅在T细胞上表达，而且在髓样细胞和树突状细胞上也表达，其中Tim3限制了 树突状细胞功能并调节抗肿瘤免疫力2。在CNS中，HAVCR2被确定为顶部之一 100个富集的成绩单，并在小鼠和人类的小胶质细胞3-5中特别表达，但其作用和 小胶质细胞中的功能尚不清楚。 我们的长期目标是定义TIM3在小胶质细胞调节神经退行性中的作用。我们做了 以下观察结果：1）TIM3抑制小胶质细胞激活和吞噬作用：tim3在树突状中的缺失 细胞增强了抗原表现，我们发现TIM3还调节小胶质细胞活化和吞噬作用。 2）TGFB-TIM3轴调节神经变性中的小胶质细胞表型开关：我们发现TGFB是关键 诱导Tim3的驱动程序，一旦表达它与TGFBR合成的驱动力 TIM3的of将M0骨底层小胶质细胞切换为MGND-Nonde-Nondebenerative表型； 3）tim3删除 小胶质细胞减少了5xFAD小鼠的斑块伯嫩。这些数据支持遗传联系研究，并显示 TIM3通过调节小胶质功能来调节AD中的疾病病理学的重要性。基于这些 研究，我们假设TIM3是小胶质细胞中的关键调节分子，可抑制其反应 到神经变性，迁移和吞噬功能，从而抑制牙菌斑清除率 导致促进AB沉积，发育和AD在衰老大脑中的发展。基于 这个假设我们提出了三个目标： 目标1：定义TIM3如何调节5xFAD和P301S鼠标AD模型中的表型和功能。我们 提议使用使用该神经变性的小胶质细胞缺失在神经变性和脑aopathy中的影响 AD的鼠标模型。 AIM 2：TGFB信号在TIM3表达和小胶质细胞中的功能中的作用是什么 和广告的开发？由于TGFB在维持体内稳态表型中起着至关重要的作用 小胶质细胞，我们建议研究TGFB信号如何诱导TIM3表达并促进体内平衡 通过与TGFB受体信号传导合作小胶质细胞的行为。 AIM 3：定义TIM3在调节AD中人类小胶质功能中的作用。确定tim3的方式 影响人IPSC衍生的小胶质细胞激活和功能。我们将检查遗传还是 TIM3的药理学抑制对表达MGND的IPSCS衍生的人类小胶质细胞具有相似的作用 通过使用人源化AD的嵌合小鼠模型进行人体抗TIM3抗体处理表型 总之，小胶质细胞中的tim3靶向可能为先天性调制提供一种新颖的方法 AD和痴呆症的免疫力。