MicroRNA regulation of central nervous system and systemic inflammation in AD

阿尔茨海默病（AD）的全球患病率不断上升，提高了开发有效治疗的紧迫性。 AD治疗。许多证据支持这一假设，即AD的发病机制涉及功能障碍， 外周和中枢神经系统（CNS）中的先天免疫效应细胞。先天免疫 促进组织修复，清除碎片，释放细胞因子和趋化因子， 与适应性免疫反应的适当接口。然而，CNS先天免疫细胞的失调， 小神经胶质细胞或外周单核细胞，有助于直接损伤突触的神经毒性环境， 形成神经损伤的前馈回路最近的技术进步产生了强大的工具， 调查先天免疫网络的分子调节剂有助于AD发病机制。微RNA，a 一类小的非编码RNA，已成为中枢神经系统和外周先天性 免疫、调节促炎活性、吞噬作用和促进Aβ清除机制。 在AD患者的脑组织、血清和CSF中，miRNA谱发生改变。特别地，miR 146和 miR 155，近端炎症调节miRNAs，在AD中表达异常，提示miRNAs参与了AD的炎症调节。 AD发病机制的炎性分支。我们小组和其他人的工作表明，miR 146和 miR 155参与体内年龄依赖性慢性炎症的发展。这些数据 强调了AD发病机制受炎性miRNA调节作用影响的假定途径 网络.在这个多PI的建议中，我们设计了一个系统的方法来研究miRNAs的作用， AD背景下的CNS和循环先天免疫细胞调节。microRNA分析，基因共- 将在外周巨噬细胞中进行表达分析和淀粉样蛋白-β（Aβ）清除研究， 从早期症状性AD和早期或无症状携带者个体分化的小胶质样细胞 家族性常染色体显性阿尔茨海默病基因（PSEN 1，PSEN 2和APP）。同时，我们将 使用鼠APP/PS1和5XFAD AD模型来确定改变的miR 146和miR 155的影响 在认知缺陷、突触丧失、Aβ清除和慢性CNS炎症中的体内表达。通过 在注定要发展的患者中捕获炎性miRNA景观和炎性特征， 阿尔茨海默型痴呆症和建模体内microRNA调节，我们的目的是确定靶向 这些通路利用CNS和外周炎症之间的双向通信。

The rising global prevalence of Alzheimer disease (AD) has heightened the urgency to develop effective AD therapeutics. Many lines of evidence support the hypothesis that AD pathogenesis involves dysfunctional innate immune effector cells in both the periphery and central nervous system (CNS). Innate immunity promotes tissue repair, clearance of debris, release of cytokines and chemokines which act to signal appropriate interface with adaptive immune responses. However, dysregulation of CNS innate immune cells, microglia, or of peripheral monocytes, contributes to a neurotoxic environment directly injuring synapses, creating a feed forward loop of neural injury. Recent technological advances have produced powerful tools to survey the molecular regulators of the innate immune network contributing to AD pathogenesis. MicroRNAs, a class of small non-coding RNAs, have emerged as powerful modulators of CNS and peripheral innate immunity, regulating pro-inflammatory activity, phagocytosis and contributing to mechanisms of Aβ clearance. MiRNA profiles are altered in brain tissue, serum and CSF of patients with AD. In particular, miR146 and miR155, proximal inflammatory modulating miRNAs, are dysregulated in AD implicating miRNAs in the inflammatory arm of AD pathogenesis. Work by our group and others have demonstrated that miR146 and miR155 participate in in the development of age-dependent chronic inflammation in vivo. These data underscore putative pathways by which AD pathogenesis is influenced by inflammatory miRNA regulatory networks. In this multi-PI proposal, we have designed a systems approach to investigate the role of miRNAs in CNS and circulating innate immune cell regulation in the context of AD. MicroRNA profiling, gene co- expression analysis and amyloid-β (Aβ) clearance studies will be performed in peripheral macrophage and microglia-like cells differentiated from individuals with early symptomatic AD and early or asymptomatic carriers of familial autosomal dominant Alzheimer disease genes (PSEN1, PSEN2 and APP). In parallel, we will employ the murine APP/PS1 and 5XFAD AD models to determine the impact of altered miR146 and miR155 expression in vivo on cognitive deficits, synapse loss, Aβ clearance and chronic CNS inflammation. By capturing the inflammatory miRNA landscape and inflammatory profile in patients destined to develop dementia of the Alzheimer type and modeling microRNA modulation in vivo, we aim to identify targetable pathways which leverage the bidirectional communication between CNS and peripheral inflammation.