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

描述（由申请人提供）： 阿尔茨海默病相关的神经退行性疾病（包括AD、PD和FTD）、肥胖和创伤性脑 所有损伤都表现出先天免疫反应不平衡。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，导致毒素释放和修复机制失败。最近的遗传关联发现暗示了两种先天免疫基因TREM 2（AD，PD，FTD）和CD 33（AD）的重要作用，表明慢性神经炎症可能是这些疾病的致病因素。AD TREM 2突变或TREM 2或其信号转导伴侣TyroBP（DAP 12）的缺失均引起异常神经炎症。此外，综合生物信息学鉴定TyroBP为与AD中改变的基因表达相关的主要信号中枢。降低CD 33（对抗TREM 2/TyroBP信号传导）可降低AD风险，而增加TREM 2/TyroBP信号传导可抑制神经毒性炎症并促进吞噬作用。我们假设在TyroBP枢纽周围恢复有效的TREM 2/CD 33信号传导将抑制痴呆中观察到的淀粉样变性和炎症驱动的tau蛋白病。我们的研究小组在AD模型中筛选了传统和替代的NSAID，并确定了一种干预措施，姜黄素，它降低了CD 33，但提高了TREM 2和TyroBP，以恢复TREM 2/CD 33平衡。这是第一个证据表明，一个小分子，有利地靶向这些新的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的淀粉样蛋白减少一致。设计图：我们建议评估这些假设使用NSAID干预在体内研究与人类E3 FAD或E4 FAD和人类tau（htau）转基因小鼠和啮齿类动物和成年人小胶质细胞。此外，我们将利用我们以前对不同NSAID方案和转基因模型的研究中的大量组织库，这些研究导致发病率增加或减少。我们还研究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相关性，这些动物研究在我们目前的姜黄素在MCI退伍军人中的试验中进行。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点，并确定预先存在的炎症环境如何影响NSAID反应性。目的1检查TREM 2/CD 33/TyroBP的调节如何在体内确定对NSAID对淀粉样蛋白或人tau负荷的双相反应，以及人CD 33水平的选择性操纵是否对抗培养的小胶质细胞中的TREM 2/TyroBP信号传导。目的2检查布洛芬和姜黄素对E3 FAD小鼠中TREM 2/CD 33的剂量依赖性短期作用以及特异性阻断TREM 2信号传导对发病机制和姜黄素功效的影响。目的3探讨参与NF？B-调节TREM 2途径在ApoE亚型依赖性反应慢性NSAID。由于肥胖增加了在衰老和tau蛋白病中发现的神经炎症，因此Aim 4将使用TREM 2诱饵测试NSAID对衰老肥胖htau Tg小鼠中TREM 2/CD 33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TREM 2/CD 33通路对A和/或NSAID的反应性（以及与啮齿动物小胶质细胞的差异，目标1B），以及姜黄素临床试验中患者PBMC细胞的反应性。可行性：我们强大的初步数据，增加的合作者，和我们的大型银行的NSAID治疗的AD动物模型脑组织表明高可行性。潜在的结果。这些目标的完成应该填补人类与啮齿动物的知识空白，并建立TREM 2/TyroBP作为先天免疫功能障碍的潜在分子靶点的作用，这些靶点可以通过选择限制NF？B或考克斯靶点。在主要AD风险因素和病理学的遗传模型中选择性调节TREM 2和CD 33将用于确定TREM 2/CD 33/TyroBP途径与发病机制的相关性。这些研究将促进创新和迫切需要的新方法来预防AD。

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.