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

描述(由申请人提供)： 与年龄相关的神经退行性疾病(包括AD、PD和FTD)、肥胖和创伤性脑 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，而慢性神经炎是由未溶解的小胶质细胞激活所驱动的，导致毒素释放和修复机制失败。最近的遗传关联发现暗示了两个先天免疫基因TREM2(AD、PD、FTD)和CD33(AD)的重要作用，这表明慢性神经炎症可能是这些疾病的一个致病因素。AD的TREM2突变或缺失或其信号转导伙伴TyroBP(DAP12)都会引起异常的神经炎症。此外，综合生物信息学发现，TyroBP是与AD基因表达改变相关的主要信号枢纽。减少CD33(与TREM2/TyroBP信号相反)降低AD风险，而增加TREM2/TyroBP信号抑制神经毒性炎症并促进吞噬功能。我们假设，恢复TyroBP中枢周围有效的TREM2/CD33信号将抑制痴呆症中出现的淀粉样变性和炎症驱动的转位症。我们的小组在AD模型中筛选了传统和替代的非甾体抗炎药，并确定了一种干预措施，姜黄素，它降低了CD33，但升高了TREM2和TyroBP，以恢复TREM2/CD33的平衡。这是第一次有一个小分子有利地针对这两个新的AD基因。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见的淀粉样蛋白减少是一致的。设计：我们建议使用非甾体抗炎药干预措施对这些假说进行体内研究，包括人类E3FAD或E4FAD和人类tau(Htau)转基因小鼠，以及啮齿动物和成年人类小胶质细胞。此外，我们将利用我们之前对不同NSAID方案和转基因模型所做的大量组织研究，这些研究导致了发病机制的增加或减少。在我们目前对患有MCI的退伍军人进行的姜黄素试验中，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记物与大脑或认知反应的相关性。目的：确定调节小胶质细胞激活的免疫调节靶点，以抑制毒性，同时保留或增强有益功能，并确定先前存在的炎症环境如何影响非甾体抗炎药的反应性。目的1研究TREM2/CD33/TyroBP的调节如何在体内决定非甾体抗炎药对淀粉样蛋白或人tau负荷的双相反应，以及选择性地操纵人CD33水平是否与培养的小胶质细胞中的TREM2/TyroBP信号相反。目的2研究布洛芬和姜黄素对E3FAD小鼠TREM2/CD33的短期剂量依赖效应，以及特异性阻断TREM2信号通路对发病机制和姜黄素疗效的影响。目的3探讨TREM2通路的核因子B调节在载脂蛋白E异构体依赖的慢性非甾体抗炎药反应中的作用。由于肥胖会增加衰老和肌萎缩症中发现的神经炎症，Aim 4将使用TREM2诱饵在老年肥胖htau TG小鼠中测试TREM2/CD33平衡的非甾体抗炎调节和作用。最后，在目标5中，我们检测了成人小胶质细胞中TREM2/CD33通路对A和/或非类固醇抗炎药(以及与啮齿动物小胶质细胞的差异，目标1B)和我们的姜黄素临床试验患者的PBMC细胞的反应性。可行性：我们强大的初步数据，合作者补充说，以及我们的大量非类固醇抗炎药治疗AD动物模型脑组织表明具有很高的可行性。潜在的后果。这些目标的完成将填补人类与啮齿动物之间的知识空白，并确立TREM2/TyroBP作为先天免疫功能障碍的潜在分子靶点(S)的作用，这种作用可以通过选择剂量限制NF？B或COX靶点的非甾体抗炎药来调节。在主要AD危险因素和病理的遗传模型中选择性地调节TREM2和CD33将被用来确定TREM2/CD33/TyroBP通路与发病机制的相关性。这些研究将促进一种创新的和迫切需要的预防AD的新方法。

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.