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: 9280836
• 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/9280836
• 关键词: Acute; Adaptor Signaling Protein; Adult; Adverse effects; Aging; Alzheimer disease prevention; 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; Enrollment; Equilibrium; Exhibits; Failure; Gene Expression; Genes; Genetic; Genetic Models; Genotype; Goals; Human; Ibuprofen; Immune; Immune System Diseases; Immune System and Related Disorders; Immunologic Markers; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Innate Immune Response; Interleukin-1; Intervention; Knockout Mice; Knowledge; Mediating; Microglia; Modeling; Molecular Target; Mus; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Non-Steroidal Anti-Inflammatory Agents; Obesity; Outcome; Parkinson Disease; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Peripheral; Peripheral Blood Mononuclear Cell; Phagocytes; Phagocytosis; Pharmaceutical Preparations; Pharmacogenetics; Phenotype; Plasmids; Play; Population; Presenile Alzheimer Dementia; Prevention trial; Production; Protein Isoforms; Regimen; Regulation; Risk; Risk Factors; Rodent; Role; Severity of illness; Signal Transduction; Surface; Synapses; System; TREM2 gene; TYROBP gene; Tauopathies; Testing; Tg2576; Therapeutic; Tissue Banks; Tissues; Toxic effect; Toxin; Transgenic Mice; Transgenic Model; Translations; Traumatic Brain Injury; Veterans; Viral Vector; age related; age related neurodegeneration; apolipoprotein E-4; base; brain tissue; cyclooxygenase 2; design; experimental study; genetic association; hTau Mice; immunoregulation; in vivo; indexing; inflammatory milieu; innate immune function; innovation; mitogen-activated protein kinase p38; neuroinflammation; neuroprotection; neurotoxic; novel strategies; outcome prediction; overexpression; predicting response; prevent; public health relevance; receptor; repaired; repository; 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）： 年龄相关的神经退行性疾病（包括 AD、PD 和 FTD）、肥胖和脑外伤 损伤都表现出不平衡的先天免疫反应。这会导致慢性神经炎症，而慢性神经炎症是由未解决的小胶质细胞激活引起的，导致毒素释放和修复机制失败。最近的遗传关联发现表明两个先天免疫基因 TREM2（AD、PD、FTD）和 CD33 (AD) 发挥着重要作用，表明慢性神经炎症可能是这些疾病的致病因素。 AD TREM2 突变或 TREM2 或其信号转导伙伴 TyroBP (DAP12) 缺失都会导致异常神经炎症。此外，综合生物信息学将 TyroBP 确定为与 AD 基因表达改变相关的主要信号中枢。减少 CD33（对抗 TREM2/TyroBP 信号传导）可降低 AD 风险，而增加 TREM2/TyroBP 信号传导可抑制神经毒性炎症并促进吞噬作用。我们假设恢复 TyroBP 中枢周围有效的 TREM2/CD33 信号传导将抑制痴呆症中出现的淀粉样变性和炎症驱动的 tau 蛋白病。我们的小组筛选了 AD 模型中的传统和替代 NSAID，并确定了一种干预措施姜黄素，它可以降低 CD33，但提高 TREM2 和 TyroBP，以恢复 TREM2/CD33 平衡。这是第一个证据表明小分子可以有利地靶向这些新的 AD 基因中的任何一个。这些数据与在接种疫苗的受试者中发现的小胶质细胞吞噬表型所观察到的淀粉样蛋白的减少一致。设计：我们建议使用 NSAID 干预体内研究对人 E3FAD 或 E4FAD 和人 tau (htau) 转基因小鼠以及啮齿动物和成人小胶质细胞进行体内研究来评估这些假设。此外，我们将利用我们之前对不同 NSAID 方案和转基因模型的研究中获得的大型组织库，这些研究导致发病机制的增加或减少。在我们目前对患有 MCI 的退伍军人进行姜黄素试验中，我们还在这些动物研究中检查了先天免疫表型的血液生物标志物与大脑或认知反应性的关联。目的：确定调节小胶质细胞活化以抑制毒性但保留或增强有益功能的免疫调节靶标，并确定预先存在的炎症环境如何影响 NSAID 反应性。目标 1 检查 TREM2/CD33/TyroBP 的调节如何决定体内淀粉样蛋白或人 tau 负荷对 NSAID 的双相反应，以及选择性操纵人 CD33 水平是否会反对培养的小胶质细胞中的 TREM2/TyroBP 信号传导。目标 2 检查布洛芬和姜黄素对 E3FAD 小鼠中 TREM2/CD33 的剂量依赖性短期影响，以及特异性阻断 TREM2 信号传导对发病机制和姜黄素功效的影响。目标 3 探讨 TREM2 通路的 NFκB 调节在对慢性 NSAID 的 ApoE 异构体依赖性反应中的参与。由于肥胖会增加衰老和 tau 蛋白病中发现的神经炎症，Aim 4 将使用 TREM2 诱饵测试 NSAID 对衰老肥胖 htau Tg 小鼠中 TREM2/CD33 平衡的调节和作用。最后，在目标 5 中，我们检查了成人小胶质细胞中 TREM2/CD33 通路对 A 和/或 NSAID 的反应性（以及与啮齿类小胶质细胞的差异，目标 1B）以及姜黄素临床试验中患者的 PBMC 细胞中的反应性。可行性：我们强有力的初步数据、更多的合作者以及我们大量的 NSAID 治疗的 AD 动物模型脑组织表明了高度的可行性。潜在的结果。这些目标的完成应填补人类与啮齿动物的知识空白，并确立 TREM2/TyroBP 作为先天性免疫功能障碍的潜在分子靶点的作用，可以通过选择 NSAIDs 以限制 NF?B 或 COX 靶点的剂量进行调节。在主要 AD 危险因素和病理学的遗传模型中选择性调节 TREM2 和 CD33 将用于确定 TREM2/CD33/TyroBP 途径与发病机制的相关性。这些研究将促进一种创新且迫切需要的 AD 预防新方法。