MicroRNA regulation of central nervous system and systemic inflammation in AD

 描述(由申请人提供)：阿尔茨海默病(AD)全球发病率的上升加剧了开发有效的AD疗法的紧迫性。许多证据支持AD发病机制与外周和中枢神经系统(CNS)中功能失调的天然免疫效应细胞有关的假说。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，这些细胞因子和趋化因子作用于与适应性免疫反应的适当接口。然而，中枢神经系统固有免疫细胞、小胶质细胞或外周单核细胞的调节失调，导致神经毒性环境直接损伤突触，形成神经损伤的前馈循环。最近的技术进步已经产生了强大的工具来调查参与AD发病的先天性免疫网络的分子调节因子。β是一类小的非编码RNA，是中枢神经系统和外周天然免疫的强大调节器，调节促炎活性、吞噬功能，并参与A microRNAs清除机制。阿尔茨海默病患者脑组织、血清和脑脊液中miRNA图谱发生改变。尤其是近端炎症调节miRNAs miR146和miR155在AD发病机制中的表达异常，提示miRNAs参与了AD发病的炎性臂。我们团队和其他人的工作表明，miR146和miR155参与了体内年龄依赖性慢性炎症的发展。这些数据强调了炎性miRNA调控网络影响AD发病的可能途径。在这个多PI的应用中，我们设计了一个系统的方法来研究在AD背景下miRNAs在中枢神经系统和循环中天然免疫细胞调节中的作用。微RNA图谱、基因共表达分析和淀粉样蛋白(Aβ，Aβ)清除研究将在从早期有症状的AD患者和家族性常染色体显性阿尔茨海默病基因(PSEN1、PSEN2和APP)的早期或无症状携带者分化出来的外周巨噬细胞和小胶质细胞样细胞中进行。同时，我们将利用小鼠APP/PS1和5XFAD模型来确定体内miR146和miR155的表达变化对认知障碍、突触丢失、Aβ清除和慢性中枢神经系统炎症的影响。通过捕获注定要发展为阿尔茨海默型痴呆的患者的炎症miRNA景观和炎症概况，并在体内对microRNA调制进行建模，我们的目标是识别利用中枢神经系统和外周炎症之间的双向沟通的有针对性的通路。

 DESCRIPTION (provided by applicant): 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 application, 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.