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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.

项目总结