Targeting the miR-155 and APOE-TREM2 pathways to restore dysfunctional microglia in Alzheimer's disease

靶向 miR-155 和 APOE-TREM2 通路以恢复阿尔茨海默病中功能失调的小胶质细胞

• 批准号: 9926784
• 负责人: Oleg Butovsky
• 金额: $ 80.93万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-15 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9926784
• 关键词: APP-PS1; Ablation; Acceleration; Address; Affect; Alleles; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; American; Amyloid beta-Protein; Animal Model; Antibodies; Apolipoprotein E; Apoptotic; Autopsy; Biological; Biology; Brain; Cells; Data; Development; Disease; Disease Progression; Equilibrium; Feedback; Functional disorder; Genes; Genetic; Goals; Health; Human; Immune; Immune system; Immunotherapeutic agent; Immunotherapy; Impairment; In Situ; Individual; Inflammatory; Inflammatory Response; Investigation; Knowledge; Lasers; Lead; MERTK gene; Mediating; MicroRNAs; Microglia; Molecular; Molecular Profiling; Molecular Target; Mononuclear; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Pathogenicity; Pathologic Processes; Pathway interactions; Peripheral; Phagocytes; Phagocytosis; Phenotype; Physiological; Play; Process; Proteins; Regulation; Risk Factors; Role; Senile Plaques; Senile dementia; Signal Pathway; Signal Transduction; TREM2 gene; Techniques; Transforming Growth Factor beta; Wild Type Mouse; analytical tool; base; brain tissue; cell type; dimer; genetic risk factor; genetic signature; humanized mouse; macrophage; monocyte; mouse model; neurodegenerative phenotype; neuroinflammation; novel; novel strategies; overexpression; recruit; restoration; stem; targeted treatment; therapeutic target; tool; transcription factor

PROJECT SUMMARY Alzheimer's disease (AD) is the most prevalent senile dementia affecting 4.5 million Americans. Neuroinflammatory changes are prominent and may significantly contribute to the pathologic process. Mononuclear phagocytes (brain resident microglia and recruited peripheral monocytes) accumulate around amyloid plaque in AD brains. However, their exact cellular identity, molecular and functional phenotypes, and their protective or destructive roles in AD are not well understood. This stems in part from the lack of a specific molecular signatures for mononuclear phagocytes, cell type-specific antibodies, and analytic tools for in situ characterization. We identified that a specific microRNA, miR-155, plays a key role in pro-inflammatory activation of microglia, whereas the TREM2/apolipoprotein E (APOE) axis plays a central role to suppress homeostatic M0 microglia. This may lead to impaired amyloid-β peptide clearance and acceleration of neurodegeneration. Thus, the balance between TREM2 and MERTK expression determines the microglial inflammatory response to apoptotic cells. Restoration of the homeostatic microglia by targeting the specific MERTK pathway represents a novel immunotherapeutic approach. Our preliminary data demonstrate that these novel molecular targets (miR-155, APOE, TREM2 and MERTK) are highly connected biological molecular regulators of microglial phenotypes and thus we will investigate each of these targets to determine their roles in AD. We hypothesize that danger signals (dead neurons and amyloid-β peptides) alter functional phenotype of innate immune cells from the homeostatic (M0) to newly discovered neurodegenerative (MGnD) phenotype. We will address our hypothesis in the following aims: Aim 1: Targeting Trem2-induced Apoe/miR155 pathway to restore M0-homeostatic microglia in AD mouse models. We will specifically delete miR-155, Apoe and Trem2 in microglia of AD mouse models. Aim 2: Restoration of M0-homeostatic microglia via Mertk pathway in humanized APOE4 and AD mice. We will specifically over-express Mertk in microglia of APOE4 humanized mice and AD mouse models. We will validate our findings by investigating AD brains from prodromal to advanced stages. The goal of our investigations is to define new molecular mechanisms of immune and inflammatory processes that contribute to the development and progression of AD, which in turn will provide a basis for new approaches for immune based therapy of the disease.

项目总结 阿尔茨海默病(AD)是最常见的老年痴呆症，影响着450万美国人。 神经炎性改变显著，可能在病理过程中起重要作用。 单核吞噬细胞(脑内驻留的小胶质细胞和招募的外周单核细胞)聚集在周围。 阿尔茨海默病大脑中的淀粉样斑块。然而，它们的确切细胞身份、分子和功能表型，以及 它们在AD中的保护性或破坏性作用还没有被很好地理解。这在一定程度上是因为缺乏一个具体的 单核巨噬细胞的分子标记、细胞类型特异性抗体和原位分析工具 人物刻画。我们发现一种特殊的microRNA miR-155在促炎中起关键作用 小胶质细胞的激活，而TREM2/载脂蛋白E(APOE)轴在抑制 动态平衡M0小胶质细胞。这可能导致淀粉样蛋白-β多肽清除受损和加速 神经退行性变。因此，TREM2和MERTK表达之间的平衡决定了小胶质细胞 对凋亡细胞的炎症反应。靶向特定的小胶质细胞修复内环境平衡的研究 MerTK途径代表了一种新的免疫治疗途径。我们的初步数据表明 这些新的分子靶点(miR-155、APOE、TREM2和MERTK)是高度联系的生物 小胶质细胞表型的分子调节器，因此我们将研究每个靶点以确定 他们在AD中的角色。我们假设危险信号(死亡神经元和淀粉样蛋白-β多肽)会改变 天然免疫细胞从稳态(M0)到新发现的功能表型 神经退行性变(MGnD)表型。我们将从以下几个方面阐述我们的假设： 目的1：靶向TREM2诱导的APOE/miR155通路恢复AD大鼠M0内环境平衡的小胶质细胞 老鼠模型。我们将特异性地缺失AD模型小鼠小胶质细胞中的miR-155、APOE和TREM2。 目的2：通过MerTK途径恢复人源化APOE4和AD小鼠M0内环境平衡的小胶质细胞。 我们将在APOE4人源化小鼠和AD模型小鼠的小胶质细胞中特异性地过表达MerTK。我们会 通过研究从先兆到晚期的阿尔茨海默病大脑来验证我们的发现。 我们研究的目标是确定免疫和炎症过程的新的分子机制。 这有助于AD的发展和进步，这反过来将为新的 基于免疫的疾病治疗方法。