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.

项目概要 最近最大的 GWAS 确定了晚发性阿尔茨海默病 (LOAD) 的 HAVCR2 (TIM3) 遗传风险因素。 我们的实验室发现并克隆了 Tim3 作为一种抑制分子，可诱导癌症中 T 细胞耗竭1。 Tim3 阻断抗体已被批准用于治疗癌症。然而，我们现在已经确定 Tim3不仅在T细胞上表达，还在骨髓细胞和树突状细胞上表达，其中TIM3抑制 树突状细胞功能和调节抗肿瘤免疫2。在 CNS 中，HAVCR2 被确定为最重要的药物之一 100 个富集转录本，在小鼠和人类小胶质细胞 3-5 中特异性表达，但其作用和 小胶质细胞的功能尚不清楚。 我们的长期目标是确定 TIM3 在神经退行性疾病中小胶质细胞调节中的作用。我们做了 以下观察结果： 1) Tim3 抑制小胶质细胞活化和吞噬作用：树突中 Tim3 的缺失 细胞增强了抗原呈递，我们发现 TIM3 还调节小胶质细胞的激活和吞噬作用； 2）TGFb-Tim3轴调节神经退行性变中小胶质细胞表型转换：我们发现TGFb是关键 Tim3 诱导的驱动因素，一旦表达，它会与 TGFBR 协同作用，增强 TGFB 信号传导、丢失 Tim3 将 M0 稳态小胶质细胞转变为 MGnD 非退行性表型； 3) TIM3 删除 小胶质细胞减少了 5xFAD 小鼠的斑块负担。这些数据支持遗传连锁研究并表明 Tim3 通过调节小胶质细胞功能来调节 AD 疾病病理学的重要性。基于这些 研究中，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 影响神经退行性变、迁移和吞噬功能，从而抑制斑块清除 从而促进老化大脑中抗体的沉积、AD的发生和进展。基于 这个假设我们提出了三个目标： 目标 1：定义 TIM3 如何在 5xFAD 和 P301S 小鼠 AD 模型中调节表型和功能。我们 提议利用以下方法研究小胶质细胞 Tim3 缺失对神经退行性变和脑 tau 病的影响 AD小鼠模型。 目标 2：TGFb 信号传导在调节小胶质细胞 Tim3 表达和功能中的作用是什么 以及AD的发展？由于 TGFb 在维持体内稳态表型中发挥着关键作用 小胶质细胞中，我们建议研究 TGFb 信号如何诱导 Tim3 表达并促进稳态 通过与 TGFb 受体信号传导合作来调节小胶质细胞的行为。 目标 3：明确 TIM3 在 AD 中人类小胶质细胞功能调节中的作用。确定TIM3如何 影响人类 iPSC 衍生的小胶质细胞的激活和功能。我们将检查是否遗传或 TIM3 的药理学抑制对表达 MGnD 的 iPSC 衍生的人小胶质细胞具有类似的作用 利用 AD 人源化嵌合小鼠模型用人抗 Tim3 抗体治疗来确定表型 总之，靶向小胶质细胞中的 TIM3 可能为先天性调节治疗提供一种新方法。 AD 和痴呆症中的免疫力。