How to modulate innate immune function to prevent age-related neurodegeneration

如何调节先天免疫功能以预防与年龄相关的神经退行性疾病

• 批准号: 8820107
• 负责人: GREGORY M COLE
• 金额: --
• 依托单位: VA GREATER LOS ANGELES HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8820107
• 关键词: Acute; Adult; Adverse effects; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid; Amyloidosis; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Apolipoprotein E; Attenuated; Bioinformatics; Biological Assay; Biological Markers; Blood; Blood Cells; Brain; Cells; Chronic; Clinical Trials; Cognitive; Complex; Curcumin; Data; Dementia; Dependence; Diet; Dose; Dose-Limiting; Enrollment; Equilibrium; Exhibits; Failure; Gene Expression; Genes; Genetic; Genetic Models; Genotype; Goals; Human; Ibuprofen; Immune; Immune System Diseases; Immune response; Immunologic Markers; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Interleukin-1; Intervention; Knowledge; Mediating; Microglia; Modeling; Molecular Target; Mus; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Non-Steroidal Anti-Inflammatory Agents; Obesity; Outcome; Parkinson Disease; Pathogenesis; Pathology; Pathway interactions; Patients; Peripheral; Peripheral Blood Mononuclear Cell; Phagocytes; Phagocytosis; Pharmaceutical Preparations; Pharmacogenetics; Phenotype; Plasmids; Play; Population; Presenile Alzheimer Dementia; Prevention; Prevention trial; Production; Protein Isoforms; Regimen; Regulation; Risk; Risk Factors; Rodent; Role; Severity of illness; Signal Transduction; Surface; Synapses; System; TYROBP gene; Tauopathies; Testing; Tg2576; Therapeutic; Tissue Banking; Tissue Banks; Tissues; Toxic effect; Toxin; Transgenic Mice; Transgenic Model; Translations; Traumatic Brain Injury; Veterans; Viral Vector; adapter protein; age related; age related neurodegeneration; apolipoprotein E-4; base; brain tissue; cyclooxygenase 2; design; genetic association; in vivo; indexing; innate immune function; innovation; mitogen-activated protein kinase p38; neuroinflammation; neuroprotection; neurotoxic; novel strategies; overexpression; prevent; public health relevance; receptor; repaired; repository; research study; response; small molecule; tau Proteins; tau-protein kinase; Acute; Adult; Adverse effects; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid; Amyloidosis; Animal Model; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Apolipoprotein E; Attenuated; Bioinformatics; Biological Assay; Biological Markers; Blood; Blood Cells; Brain; Cells; Chronic; Clinical Trials; Cognitive; Complex; Curcumin; Data; Dementia; Dependence; Diet; Dose; Dose-Limiting; Enrollment; Equilibrium; Exhibits; Failure; Gene Expression; Genes; Genetic; Genetic Models; Genotype; Goals; Human; Ibuprofen; Immune; Immune System Diseases; Immune response; Immunologic Markers; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Interleukin-1; Intervention; Knowledge; Mediating; Microglia; Modeling; Molecular Target; Mus; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Non-Steroidal Anti-Inflammatory Agents; Obesity; Outcome; Parkinson Disease; Pathogenesis; Pathology; Pathway interactions; Patients; Peripheral; Peripheral Blood Mononuclear Cell; Phagocytes; Phagocytosis; Pharmaceutical Preparations; Pharmacogenetics; Phenotype; Plasmids; Play; Population; Presenile Alzheimer Dementia; Prevention; Prevention trial; Production; Protein Isoforms; Regimen; Regulation; Risk; Risk Factors; Rodent; Role; Severity of illness; Signal Transduction; Surface; Synapses; System; TYROBP gene; Tauopathies; Testing; Tg2576; Therapeutic; Tissue Banking; Tissue Banks; Tissues; Toxic effect; Toxin; Transgenic Mice; Transgenic Model; Translations; Traumatic Brain Injury; Veterans; Viral Vector; adapter protein; age related; age related neurodegeneration; apolipoprotein E-4; base; brain tissue; cyclooxygenase 2; design; genetic association; in vivo; indexing; innate immune function; innovation; mitogen-activated protein kinase p38; neuroinflammation; neuroprotection; neurotoxic; novel strategies; overexpression; prevent; public health relevance; receptor; repaired; repository; research study; response; small molecule; tau Proteins; tau-protein kinase

DESCRIPTION (provided by applicant): Age-related neurodegenerative diseases (including AD, PD and FTD), obesity and traumatic brain injury all exhibit imbalanced innate immune responses. This contributes to chronic neuroinflammation, which is driven by unresolved microglial activation, leading to toxin release and failed repair mechanisms. Recent genetic-association discoveries imply an important role for two innate immune genes, TREM2 (for AD, PD, FTD) and CD33 (AD), suggesting chronic neuroinflammation may be a causative factor in these conditions. Both the AD TREM2 mutation or loss of TREM2 or its signal transduction partner, TyroBP (DAP12), cause aberrant neuroinflammation. Furthermore, integrated bioinformatics identify TyroBP as the major signaling hub associated with altered gene expression in AD. Decreasing CD33 (which opposes TREM2/TyroBP signaling) reduces AD risk, while increasing TREM2/TyroBP signaling suppresses neurotoxic inflammation and promotes phagocytosis. We hypothesize that restoring effective TREM2/CD33 signaling around the TyroBP hub will suppress the amyloidosis and inflammation-driven tauopathy seen in dementia. Our group screened conventional and alternative NSAIDs in AD models and identified an intervention, curcumin, that lowers CD33 but raises TREM2 and TyroBP to restore the TREM2/CD33 balance. This is the first evidence of a small molecule that favorably targets either of these new AD genes. These data are consistent with the reductions in amyloid seen with the microglial phagocytic phenotype found in Avaccinated subjects. Design: We propose to evaluate these hypotheses using NSAID interventions in vivo studies with human E3FAD or E4FAD and human tau (htau) transgenic mice and with rodent and adult human microglia. In addition we will take advantage of our large repository of tissue from our prior studies of different NSAID regimens and transgenic models, which resulted in increased or decreased pathogenesis. We also examine associations of blood biomarkers of innate immune phenotypes with brain or cognitive responsiveness in these animal studies in our current trial of curcumin in Veterans with MCI. Objectives: To identify immunomodulatory targets that modulate microglial activation to suppress toxicity yet retain or enhance beneficial functions, and to determine how the pre-existing inflammatory milieu impacts NSAID responsiveness. Aim 1 examines how modulation of TREM2/CD33/TyroBP determines biphasic responses to NSAID on amyloid or human tau burden in vivo and if selective manipulation of human CD33 levels opposes TREM2/TyroBP signaling in cultured microglia. Aim 2 examines dose-dependent short term effects of ibuprofen and curcumin on TREM2/CD33 in E3FAD mice and the impact of specifically blocking TREM2 signaling on pathogenesis and curcumin efficacy. Aim 3 explores the involvement of NF?B-regulation of the TREM2 pathway in ApoE isoform-dependent responses to chronic NSAIDs. Since obesity increases neuroinflammation found in aging and tauopathy, Aim 4 will test NSAID modulation of and role of TREM2/CD33 balance in aging obese htau Tg mice using a TREM2 decoy. Finally, in Aim 5, we examine the responsiveness of the TREM2/CD33 pathway in adult human microglia to Aand/or NSAIDs (and differences with rodent microglia, Aim 1B) and in PBMC cells from patients in our curcumin clinical trial. Feasibility: Our strong preliminary data, added collaborators, and our large bank of NSAID treated AD animal model brain tissue suggest high feasibility. Potential Outcomes. Completion of these aims should fill human vs. rodent knowledge gaps and establish the roles of TREM2/TyroBP as potential molecular target(s) of innate immune dysfunction that can be modulated by select NSAIDs at doses that limit either NF?B or COX targets. Selectively modulating TREM2 and CD33 in genetic models of the major AD risk factors and pathologies will be used to determine the relevance of TREM2/CD33/TyroBP pathways to pathogenesis. These studies will facilitate an innovative and urgently needed new approach to AD prevention.

描述（由申请人提供）： 与年龄有关的神经退行性疾病（包括AD，PD和FTD），肥胖和创伤性脑 伤害均表现出不平衡的先天免疫反应。这有助于慢性神经炎症，这是由未解决的小胶质细胞激活驱动的，导致毒素释放和失败的修复机制。最近的遗传关联发现暗示了两个先天免疫基因TREM2（对于AD，PD，FTD）和CD33（AD）的重要作用，这表明在这些条件下，慢性神经炎症可能是一个病因。 AD TREM2突变或TREM2或其信号转导伴侣Tyrobp（DAP12）都会引起异常神经炎症。此外，综合的生物信息学识别Tyrobp是与AD中基因表达改变有关的主要信号枢纽。降低CD33（反对TREM2/TyroBP信号传导）会降低AD风险，同时增加Trem2/Tyrobp信号传导抑制神经毒性炎症并促进吞噬细胞增多症。我们假设恢复TyroBP枢纽周围有效的Trem2/CD33信号传导将抑制痴呆症中观察到的淀粉样变性和炎症驱动的tauopathy。我们的小组在AD模型中筛选了常规和替代NSAID，并确定了一种干预措施，该干预措施降低了CD33，但提高了TREM2和TyroBP以恢复TREM2/CD33的平衡。这是一个小分子的第一个证据，该分子靶向这些新的AD基因之一。这些数据与淀粉样蛋白的降低是一致的，该淀粉样蛋白与在AVACCCACTAIND受试者中发现的小胶质细胞吞噬表型相一致。设计：我们建议使用人类E3FAD或E4FAD和人Tau（HTAU）转基因小鼠以及啮齿动物和成年人的人类小胶质细胞在体内研究中评估这些假设。此外，我们将从先前对不同NSAID方案和转基因模型的研究中利用我们的大型组织存储库，从而导致发病机理增加或减少。我们还研究了当前对MCI退伍军人的姜黄素试验，在这些动物研究中，在这些动物研究中，先天性免疫表型与大脑或认知反应能力的血液生物标志物的关联。目的：确定调节小胶质激活以抑制毒性但保留或增强有益功能的免疫调节靶标，并确定现有的炎症环境如何影响NSAID的反应性。 AIM 1检查了TREM2/CD33/Tyrobp的调节如何确定对体内淀粉样蛋白或人tau负担的NSAID的双相反应，以及对人CD33水平的选择性操纵是否反对培养的小胶质细胞中的Trem2/Tyrobp信号传导。 AIM 2检查了布洛芬和姜黄素对E3FAD小鼠中TREM2/CD33的剂量依赖性短期影响，以及专门阻断TREM2信号对发病机理和姜黄素疗效的影响。 AIM 3探讨了NF？B调节的TREM2途径在APOE同工型依赖于慢性NSAIDS中的参与。由于肥胖会增加在衰老和tauopathy中发现的神经炎症，因此AIM 4将使用Trem2诱饵测试TREM2/CD33平衡在衰老肥胖HTAU TG小鼠中的NSAID调节和作用。最后，在AIM 5中，我们检查了成人人类小胶质细胞中TREM2/CD33途径对AAND/或NSAID（以及啮齿动物小胶质细胞的差异，AIM 1B）以及我们姜黄素临床试验中患者的PBMC细胞的反应性。可行性：我们强大的初步数据，添加了合作者，以及我们大量的NSAID AD AD AD ANDINAL模型脑组织的可行性。潜在的结果。这些目标的完成应填补人类与啮齿动物知识差距，并确定trem2/tyrobp作为先天免疫功能障碍的潜在分子靶标的作用，可以通过限制NF？b或cox靶标的剂量来调节这些差异。在主要的AD风险因素和病理学的遗传模型中有选择地调节TREM2和CD33将用于确定TREM2/CD33/TyroBP途径与发病机理的相关性。这些研究将促进一种创新的，急需的新方法来预防广告。