Rebalancing Innate Immunity in Alzheimer's disease by deleting IRAK-M

项目总结/摘要 虽然淀粉样蛋白斑块和神经纤维缠结是阿尔茨海默病（AD）的特征， 阿尔茨海默氏症自己最初确定了第三种病理-神经胶质炎症。AD神经炎症是 特征为围绕淀粉样斑块的反应性星形胶质细胞和小胶质细胞， 促炎性先天免疫细胞因子的水平。几十年来的主流观点一直是， 炎症损害AD大脑。然而，阻断炎症是有益的这种简单化的概念并没有 非甾体类抗炎药不能对AD的一级预防产生积极的信号。 这就提出了一个根本性的问题：先天免疫系统真的可以被用作AD吗 治疗性的？虽然焦点一直直接放在促炎分子上，但很少有人关注 抑制先天免疫反应的因素。我们工作的统一主题是“再平衡” 脑先天免疫通过释放免疫抑制将限制AD的进展。我们专注于 最近，全基因组关联研究证实了AD中的免疫性，该研究在该领域引起了轰动 通过鉴定属于核心先天免疫和炎症途径的AD风险等位基因簇。 Toll样受体（TLR），入侵病原体和内源性危险的种系编码传感器- 相关分子模式（DAMP）在很大程度上负责先天免疫应答。安装 有证据表明淀粉样蛋白-β作为DAMP引起小胶质细胞TLR信号传导。TLR抑制剂 通过白细胞介素-1受体相关激酶（IRAKs）信号，IRAK-M是唯一的IRAK家族 抑制TLR信号传导的成员。重要的是，IRAK-M由单核细胞选择性表达。 吞噬细胞（例如，小胶质细胞和巨噬细胞）。我们的初步数据表明， TRAF 6/MEKK 3通路在人类AD中异常升高，并且IRAK-M缺失允许A β吞噬作用。 在本研究中，我们将通过基因缺失APP/PS1中的IRAK-M来缓解TLR信号传导抑制， 小鼠脑淀粉样变性模型。我们的总体假设是，释放IRAK-M抑制先天性 免疫将有益地激活淀粉样蛋白-β吞噬作用并恢复认知功能。具体目标1、 认知障碍、AD样病理学和Aβ/β-淀粉样蛋白吞噬作用（使用我们的新型q3 DISM技术） 将在APP/PS1 x IRAK-M缺陷型小鼠中进行评价。此外，我们将分离脑单核细胞， 通过转录组学进行先天免疫表型分型（RNAseq）。在具体目标2中，我们将确定相对 外周与中枢先天免疫区室对骨髓嵌合体的贡献。 该项目的完成将导致对AD背景下先天免疫的更深入，基本的理解。

PROJECT SUMMARY/ABSTRACT While amyloid plaques and neurofibrillary tangles are Alzheimer’s disease (AD) pathognomonic features, Alzheimer himself originally identified a third pathology–glial inflammation. AD neuroinflammation is characterized by reactive astrocytes and microglia that surround amyloid plaques and chronically secrete low levels of pro-inflammatory innate immune cytokines. The dominant view for decades has been that all forms of inflammation damage the AD brain. Yet, the simplistic notion that blocking inflammation is beneficial has not held up–non-steroidal anti-inflammatory drugs failed to produce a positive signal for AD primary prevention. This raises a fundamental question: could the innate immune system actually be harnessed as an AD therapeutic? While the focus has squarely been on pro-inflammatory molecules, little attention has been paid to factors that suppress the innate immune response. The unifying theme of our work is that ‘rebalancing’ cerebral innate immunity by releasing immunosuppression will limit AD progression. Our focus on innate immunity in AD has recently been validated by genome-wide association studies, which took the field by storm by identifying a cluster of AD risk alleles belonging to core innate immune and inflammation pathways. Toll-like receptors (TLRs), germline-encoded sensors of invading pathogens and endogenous danger- associated molecular patterns (DAMPs), are largely responsible for innate immune responses. Mounting evidence has shown that amyloid-β acts as a DAMP to provoke microglial TLR signaling. TLRs transduce their signals through interleukin-1 receptor-associated kinases (IRAKs), and IRAK-M is the only IRAK family member that suppresses TLR signaling. Importantly, IRAK-M is selectively expressed by mononuclear phagocytes (e.g., microglia and macrophages). Our preliminary data demonstrate that the IRAK-associated TRAF6/MEKK3 pathway is abnormally elevated in human AD, and IRAK-M deletion licenses A phagocytosis. In this proposal, we will relieve TLR signaling inhibition by genetic deletion of IRAK-M in the APP/PS1 mouse model of cerebral amyloidosis. Our overarching hypothesis is that releasing IRAK-M inhibition of innate immunity will beneficially activate amyloid-β phagocytosis and restore cognitive function. In Specific Aim 1, cognitive impairment, AD-like pathology and Aβ/β-amyloid phagocytosis (using our novel q3DISM technology) will be evaluated in APP/PS1 x IRAK-M deficient mice. Further, we will isolate brain monocytes and perform innate immune phenotyping by transcriptomics (RNAseq). In Specific Aim 2, we will determine the relative contribution(s) of peripheral verses central innate immune compartments with bone marrow chimeras. Completion of this project will lead to a deeper, basic understanding of innate immunity in the context of AD.