Investigating the role of microRNAs in microglia in a mouse model of Alzheimerâs Disease

项目总结/摘要 阿尔茨海默氏病是痴呆的主要原因，其病理特征是细胞外 淀粉样斑块、脑中的tau蛋白聚集体和小神经胶质增生。小胶质细胞是固有的 中枢神经系统（CNS）的免疫细胞和最近的全基因组关联研究已经将 小胶质细胞基因突变增加了患迟发性阿尔茨海默病的风险。的一个主要 小胶质细胞的功能是吞噬细胞清除碎片，包括细胞外tau，和小胶质细胞摄取tau 与tau蛋白病理学有关因此，更深入地了解小胶质细胞吞噬作用及其 疾病中的调节对于理解阿尔茨海默病中tau聚集的机制是必要的 并确定新的治疗靶点。microRNAs（miRNAs）是一种小的非编码RNA， 它们的靶mRNA的翻译，并且它们的表达已被证明在AD患者中失调， 其中一些针对先天免疫途径。然而，目前还不清楚miRNAs在 小胶质细胞调节细胞功能以及小胶质细胞miRNA是否可以调节tau病理。 我们的初步研究表明，小胶质细胞中成熟miRNAs的丢失会加重男性中tau蛋白的病理学变化。 tau蛋白病小鼠我们假设小胶质细胞中miRNAs的缺失降低了细胞降解tau蛋白的能力， 导致细胞外tau蛋白增加，并加剧神经元中tau蛋白的聚集。在本提案中，我们 两个目的是测试这个假设。在目标1中，我们将检验以下假设： 小胶质细胞降低了细胞在体外和体内降解tau的能力。在目标2中，我们将检验假设 在小胶质细胞中表达最高的miRNA，miR-16- 5 p，是降解神经胶质细胞所必需的，也是足够的。 Tau蛋白通过microgila表达，并且可以在体内调节Tau蛋白病理学。这些实验将揭示miRNA- 调节tau吞噬和降解及其对tau聚集的贡献。完成这些 aims将深入了解在tau蛋白病中调节先天免疫系统的新途径， 在阿尔茨海默病中基于miRNA的治疗的潜在靶点。

Project Summary/Abstract Alzheimer's Disease is the leading cause of dementia and is pathologically characterized by extracellular amyloid plaques, tau protein aggregates in the brain, and microgliosis. Microglia are the resident innate immune cells of the central nervous system (CNS) and recent genome-wide association studies have linked mutations in microglial genes to increased risk of developing late-onset Alzheimer's Disease. One of the main functions of microglia is phagocytic clearance of debris including extracellular tau, and microglia uptake of tau has been implicated in tau pathology. Therefore, a deeper understanding of microglial phagocytosis and its regulation in disease is necessary to understand the mechanism of tau aggregation in Alzheimer's Disease and to identify new therapeutic targets. MicroRNAs (miRNAs) are small, non-coding RNAs that inhibit translation of their target mRNAs, and their expression has been shown to be dysregulated in AD patients with some of these miRNAs targeting innate immune pathways. It is, however, not well understood what miRNAs in microglia modulate cell function and whether microglial miRNAs can modulate tau pathology. Our preliminary studies show that loss of mature miRNAs in microglia exacerbates tau pathology in male tauopathy mice. We hypothesize that loss of miRNAs in microglia decreases the cell's ability to degrade tau, leading to increases in extracellular tau, and exacerbating aggregation of tau in neurons. In this proposal, we outline two aims to test this hypothesis. In Aim 1, we will test the hypothesis that loss of mature miRNAs in microglia decreases the cell's capacity to degrade tau in vitro and in vivo. In Aim 2, we will test the hypothesis that the most highly-expressed miRNA in microglia, miR-16-5p, is necessary and sufficient for degradation of tau by microgila and can modulate tau pathology in vivo. These experiments will shed insight onto miRNA- regulation of tau phagocytosis and degradation and its contribution to tau aggregation. Completion of these aims will yield insights into new pathways regulating the innate immune system in tauopathies and uncover potential targets for miRNA-based therapeutics in Alzheimer's Disease.