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: 9219386
• 负责人: Oleg Butovsky
• 金额: $ 82.86万
• 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/9219386
• 关键词: APP-PS1; Ablation; Acceleration; Address; Affect; Alleles; Alzheimer' s Disease; Alzheimer' s disease model; American; Amyloid beta-Protein; Animal Model; Antibodies; Apolipoprotein E; Apoptotic; Autopsy; Biological; Biology; Brain; Brain Diseases; Cells; Data; Development; Dimerization; Disease; Disease Progression; Equilibrium; Feedback; Functional disorder; Genes; Genetic; Goals; Health; Human; Immune; Immune system; Immunotherapeutic agent; 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; Recruitment Activity; 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; 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.

项目摘要 阿尔茨海默氏病（AD）是影响450万美国人的最普遍的老年痴呆症。 神经炎性变化是突出的，并可能显着有助于病理过程。 单核吞噬细胞（脑内驻留的小胶质细胞和募集的外周单核细胞）聚集在周围 AD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， 它们在AD中的保护性或破坏性作用还不清楚。这部分是由于缺乏一个具体的 单核吞噬细胞的分子标记、细胞类型特异性抗体和原位分析工具 特征化我们发现一种特异性的microRNA，miR-155，在促炎症反应中起着关键作用。 小胶质细胞的激活，而TREM 2/载脂蛋白E（APOE）轴在抑制小胶质细胞的激活中起着重要作用。 稳态M0小胶质细胞。这可能导致淀粉样β肽清除受损和加速 神经变性因此，TREM 2和MERTK表达之间的平衡决定了小胶质细胞的增殖。 对凋亡细胞的炎症反应。通过靶向特异性靶点恢复稳态小胶质细胞 MERTK途径代表了一种新的免疫途径。我们的初步数据表明， 这些新的分子靶点（miR-155、APOE、TREM 2和MERTK）是高度相关的生物学靶点， 小胶质细胞表型的分子调节因子，因此我们将研究这些靶点中的每一个，以确定 在AD中的角色我们假设危险信号（死亡神经元和淀粉样β肽）改变了 先天免疫细胞的功能表型从稳态（M0）到新发现的 神经退行性（MGnD）表型。我们将在以下目标中阐述我们的假设： 目的1：靶向Trem 2诱导的Apoe/miR 155通路以恢复AD中的M0稳态小胶质细胞 小鼠模型。我们将在AD小鼠模型的小胶质细胞中特异性地删除miR-155、Apoe和Trem 2。 目的2：在人源化APOE 4和AD小鼠中通过Mertk途径恢复M0稳态小胶质细胞。 我们将在APOE 4人源化小鼠和AD小鼠模型的小胶质细胞中特异性过表达Mertk。我们将 通过研究AD患者从前驱期到晚期的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分子机制 这有助于AD的发展和进步，反过来又将为新的 用于疾病的基于免疫的治疗的方法。