Essential roles of DAP12 in tau metabolism and inflammation in Alzheimer's disease

DAP12 在阿尔茨海默病 tau 代谢和炎症中的重要作用

基本信息

批准号：
10222550
负责人：
WENJIE LUO
金额：
$ 42.38万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10222550
关键词：
AD transgenic mice Adaptor Signaling Protein Affect Alzheimer&apos s Disease Binding Brain Cell Nucleus Complement 1q Complement 4b Complex Cytometry Data Dementia Development Disease Dissociation Elderly Event Genes Genetic Gliosis Goals Human Immune Immune response Immunologic Receptors In Vitro Inflammation Inflammatory Inflammatory Response Lentivirus Vector MAP Kinase Gene MAPK8 gene Macrophage-1 Antigen Mediating Metabolism Microglia Molecular Mus Natural Immunity Neurons Pathogenesis Pathogenicity Pathology Pathway interactions Phagocytes Phagocytosis Phenocopy Phosphorylation Play Proteins Regulation Role Signal Pathway Signal Transduction Signal Transduction Pathway Spatial Distribution Specificity Stimulus Surface System TREM2 gene TYRO Protein Tyrosine Kinase Binding Protein TYROBP gene Tauopathies Testing Therapeutic Intervention Transgenic Mice age group brain cell cell type complement pathway cytokine early onset effective therapy extracellular genetic signature high resolution imaging in vivo induced pluripotent stem cell knock-down mouse model mutant novel therapeutic intervention overexpression p38 Mitogen Activated Protein Kinase receptor response tau Proteins transcriptome transcriptome sequencing transcriptomics uptake

AD transgenic mice Adaptor Signaling Protein Affect Alzheimer&apos s Disease Binding Brain Cell Nucleus Complement 1q Complement 4b Complex Cytometry Data Dementia Development Disease Dissociation Elderly Event Genes Genetic Gliosis Goals Human Immune Immune response Immunologic Receptors In Vitro Inflammation Inflammatory Inflammatory Response Lentivirus Vector MAP Kinase Gene MAPK8 gene Macrophage-1 Antigen Mediating Metabolism Microglia Molecular Mus Natural Immunity Neurons Pathogenesis Pathogenicity Pathology Pathway interactions Phagocytes Phagocytosis Phenocopy Phosphorylation Play Proteins Regulation Role Signal Pathway Signal Transduction Signal Transduction Pathway Spatial Distribution Specificity Stimulus Surface System TREM2 gene TYRO Protein Tyrosine Kinase Binding Protein TYROBP gene Tauopathies Testing Therapeutic Intervention Transgenic Mice age group brain cell cell type complement pathway cytokine early onset effective therapy extracellular genetic signature high resolution imaging in vivo induced pluripotent stem cell knock-down mouse model mutant novel therapeutic intervention overexpression p38 Mitogen Activated Protein Kinase receptor response tau Proteins transcriptome transcriptome sequencing transcriptomics uptake

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项目摘要

PROJECT SUMMARY Alzheimer’s disease is the most common cause of dementia in the elderly. Recent genetic data strongly suggest that microglia-mediated innate immune activities may directly contribute to the AD mechanisms at early onset and/or developmental stage of this disease. Understanding the molecular mechanisms underpinning how microglia are functionally involved in the pathogenesis of AD is beneficial for the development of new therapeutic strategies for AD. Our long-term objective is to dissect the function of adaptor protein DAP12 in mediating complex signals and executing their functions in microglia involved in AD pathogenesis. Our preliminary data revealed a global effect of DAP12 deficiency in the brain transcriptome of tau P301S mouse, which reverses the transcriptomic changes featured in the brains of multiple AD transgenic mouse models. We further found that DAP12 deficiency increased brain tau pathology in tau P301S mice and reduced tau degradation by cultured primary microglia. Yet, DAP12 deficiency significantly decreased brain microgliosis in tau P301S mice. Therefore, we hypothesize that DAP12 plays differential roles in tau metabolism and microglia-mediated inflammation during the pathogenesis of AD. We plan to fully characterize the role of DAP12 in these two AD- relevant cellular events mediated by microglia and tau seeding/spreading. Finally we will further determine signaling pathways altered by DAP12 deficiency on cell type specific manner in tauopathy mice.

项目摘要阿尔茨海默氏病是老年痴呆症最常见的原因。最近的遗传数据强烈建议小胶质细胞介导的先天免疫活动可能直接有助于早期发作的AD机制和/或这种疾病的发育阶段。了解如何支撑的分子机制小胶质细胞在功能上与AD发病机理有关，对新治疗的发展有益广告策略。我们的长期目标是剖析介导中衔接蛋白DAP12的功能复杂的信号并执行与AD发病机理有关的小胶质细胞中的功能。我们的初步数据揭示了DAP12缺乏症在Tau P301S小鼠的脑转录组中的全球影响，这逆转了多个AD转基因小鼠模型的大脑中的转录组变化。我们进一步发现 DAP12缺乏增加了tau P301S小鼠中的脑tau病理，并通过培养原发性小胶质细胞。然而，DAP12缺乏症显着降低了Tau P301S小鼠的脑小胶质细胞增多症。因此，我们假设DAP12在TAU代谢和小胶质细胞介导的 AD发病机理期间的炎症。我们计划充分表征DAP12在这两个ad-中的作用由小胶质细胞和tau播种/扩散介导的相关细胞事件。最后，我们将进一步确定 DAP12缺乏在tauopathy小鼠的细胞类型特异性方式上改变了信号通路。