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：
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
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/9926784
关键词：
APP-PS1 Ablation Acceleration Address Affect Alleles Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos 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

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.

项目概要阿尔茨海默病 (AD) 是最常见的老年痴呆症，影响着 450 万美国人。神经炎症变化很突出，并且可能显着促进病理过程。单核吞噬细胞（大脑驻留的小胶质细胞和招募的外周单核细胞）聚集在周围然而，AD 大脑中的淀粉样蛋白斑块的确切细胞特性、分子和功能表型以及它们在 AD 中的保护或破坏作用尚不清楚，部分原因是缺乏具体的信息。单核吞噬细胞的分子特征、细胞类型特异性抗体和原位分析工具我们发现一种特定的 microRNA，miR-155，在促炎中发挥着关键作用。小胶质细胞的激活，而 TREM2/载脂蛋白 E (APOE) 轴在抑制稳态 M0 小胶质细胞可能会导致淀粉样蛋白 β 肽清除受损并加速。因此，TREM2 和 MERTK 表达之间的平衡决定了小胶质细胞的发生。通过针对特定的小胶质细胞恢复稳态的炎症反应。 MERTK 通路代表了一种新型免疫治疗方法。我们的初步数据表明。这些新的分子靶标（miR-155、APOE、TREM2 和 MERTK）在生物学上高度相关小胶质细胞表型的分子调节因子，因此我们将研究每个目标以确定我们捕捉到了危险信号（死亡神经元和淀粉样β肽）的变化。先天免疫细胞的功能表型从稳态（M0）到新发现我们将通过以下目标来解决我们的假设：目标 1：靶向 Trem2 诱导的 Apoe/miR155 通路以恢复 AD 中 M0 稳态小胶质细胞我们将特意删除 AD 小鼠模型小胶质细胞中的 miR-155、Apoe 和 Trem2。目标 2：在人源化 APOE4 和 AD 小鼠中通过 Mertk 途径恢复 M0 稳态小胶质细胞。我们将在 APOE4 人源化小鼠和 AD 小鼠模型的小胶质细胞中特异性过度表达 Mertk。通过研究从前驱期到晚期阶段的 AD 大脑来验证我们的发现。我们研究的目标是定义免疫和炎症过程的新分子机制有助于AD的发展和进展，反过来又将为新的AD提供基础基于免疫的疾病治疗方法。