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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos 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

项目摘要

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。神经炎症的变化是显着的，并且可能有助于病理过程。单核吞噬细胞（脑居民小胶质细胞和招募的外周单核细胞）堆积在周围广告大脑中的淀粉样斑块。但是，它们的确切细胞身份，分子和功能表型以及他们在AD中受到保护或破坏性的作用尚不清楚。这部分是由于缺乏特定的单核吞噬细胞，细胞类型特异性抗体和原位分析工具的分子特征表征。我们确定特定的microRNA miR-155在促炎中起关键作用小胶质细胞的激活，而Trem2/apoleipoprotin e（APOE）轴均起着抑制的核心作用稳态M0小胶质细胞。这可能导致淀粉样β肽清除和加速度受损神经变性。这，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。通过靶向特定的稳态小胶质细胞恢复 MERTK途径代表了一种新型的免疫治疗方法。我们的初步数据表明这些新型的分子靶标（miR-155，ApoE，Trem2和Mertk）是高度连接的生物学小胶质表型的分子调节剂，因此我们将研究这些目标中的每一个以确定他们在广告中的角色。我们假设危险信号（死神经元和淀粉样蛋白-β肽）改变从稳态（M0）到新发现的先天免疫细胞的功能表型神经退行性（MGND）表型。我们将在以下目的中解决我们的假设： AIM 1：靶向TREM2诱导的APOE/MIR155途径，以恢复AD中的M0骨小胶质细胞鼠标模型。我们将在AD小鼠模型的小胶质细胞中特别删除miR-155，APOE和TREM2。 AIM 2：通过人源化APOE4和AD小鼠中M0骨层小胶质细胞的恢复。我们将在APOE4人源化小鼠和AD小鼠模型的小胶质细胞中特别过表达MERTK。我们将通过调查从前驱阶段到高级阶段的广告大脑来验证我们的发现。我们调查的目的是定义免疫和炎症过程的新分子机制这有助于AD的发展和发展，这反过来将为新的基础提供基础基于免疫的疾病治疗方法。