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

项目摘要/摘要 虽然淀粉样斑块和神经原纤维缠结是阿尔茨海默病(AD)的病因特征， 阿尔茨海默氏症自己最初发现了第三种病理--神经胶质炎症。AD神经炎是 以反应性星形胶质细胞和小胶质细胞围绕淀粉样斑块并慢性分泌低为特征 促炎症先天免疫细胞因子水平。几十年来，占主导地位的观点一直是所有形式的 炎症会损害阿尔茨海默病的大脑。然而，认为阻断炎症有益的简单化观念并没有 受阻--非类固醇抗炎药未能对AD一级预防产生积极信号。 这提出了一个根本的问题：先天免疫系统真的可以被利用为阿尔茨海默病吗 治疗？虽然焦点一直集中在促炎分子上，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’ 大脑的先天免疫通过释放免疫抑制来限制AD的进展。我们对先天的关注 最近，全基因组关联研究证实了阿尔茨海默病的免疫力，该研究在该领域掀起了一场风暴 通过识别一组AD风险等位基因，这些等位基因属于核心的先天免疫和炎症途径。 Toll样受体(TLRs)，入侵病原体和内源性危险的生殖线编码传感器- 相关的分子模式(DAMP)在很大程度上对先天免疫反应负责。安装 有证据表明，淀粉样蛋白-β作为一种阻尼剂，可以激发小胶质细胞的TLR信号。TLR将他们的 通过白介素1受体相关激酶(IRAK)传递信号，IRAK-M是唯一的IRAK家族 抑制TLR信令的成员。重要的是，IRAK-M是通过单核细胞选择性表达的 吞噬细胞(如小胶质细胞和巨噬细胞)。我们的初步数据显示，与伊拉克有关的 TRAF6/MEKK3通路在人AD中异常升高，IRAK-M缺失允许A吞噬。 在这项建议中，我们将通过APP/PS1中IRAK-M的基因缺失来解除TLR信号抑制 小鼠脑淀粉样变性模型。我们的主要假设是释放IRAK-M对先天的抑制 免疫将有益于激活淀粉样蛋白β吞噬功能，恢复认知功能。在具体目标1中， 认知障碍、AD样病理和β/β-淀粉样吞噬(使用我们的新Q3DISM技术) 将在APP/PS1×IRAK-M缺陷小鼠身上进行评估。此外，我们将分离大脑单核细胞并进行 天然免疫转录组表型(RNAseq)。在具体目标2中，我们将确定相对 骨髓嵌合体的外周和中枢天然免疫隔室的贡献(S)。 该项目的完成将使我们对AD背景下的先天免疫有一个更深入、更基本的了解。

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.