MicroRNA lipid-nanoparticle based therapy targets neuroinflammation and ApoE dysregulation in Alzheimer’s disease

项目名称：基于MicroRNA脂质纳米颗粒的治疗靶向神经炎症和ApoE失调 在阿尔茨海默病中 摘要 MicroRNA（miRNA）是一类小的非编码调控RNA，对健康和疾病有重要影响。 虽然先前的研究表明miRNA与阿尔茨海默病和相关痴呆症（ADRD）有关，但他们发现， 尚未被用于成功的治疗策略。我们发现microRNA-223（miR-223），一种 存在于小胶质细胞/巨噬细胞中富集的X染色体上的miRNA，调节性分化。 通过靶向CCAAT-增强子结合蛋白β（CEBPβ）的双态ApoE途径。CEBPβ是一种重要的 调节神经炎症反应，并作为转录因子介导ApoE表达。 我们最近的数据显示，miR-223的缺乏导致了显著的、女性偏向的 CEBPβ，ApoE，以及巨噬细胞和老年小鼠脑中的炎症状态升高， 脑损伤因此，miR-223似乎调节性二态性小胶质细胞/巨噬细胞依赖性 炎症和ApoE增加，因为脑细胞与年龄、损伤和/或 阿尔茨海默病相关的病理学。我们进一步证明了miR-223可以用一种新的靶向方法来靶向。 miRNA-脂质体递送系统。基于这些令人兴奋的初步结果，本提案的主要目标 检测miR-223-CEBPβ通路在调节炎症触发的ApoE失调中的作用， 年龄、性别和阿尔茨海默病相关脑损伤事件的生物学背景;以及，为了测试 新的脂质体-miRNA递送方法作为潜在的治疗策略。 为了完成这些目标，我们将1）证实miR-223直接靶向CEBPβ-ApoE通路， 骨髓细胞，并测试脂质体-miR-223递送是否影响该途径; 2）测试miR-223-CEBPβ- ApoE通路使用脑损伤小鼠模型并靶向该通路使用脂质体递送miRNA 3）评估miR-223-CEBPβ-ApoE通路在人细胞中的作用， 与阿尔茨海默病的神经病理学改变相平行。这些研究将包括评估 来自世界一流的肯塔基州大学阿尔茨海默病中心生物库的脑组织。 完成资助的研究将扩大我们对调节机制的理解， 炎症/ApoE通路在性别，衰老和脑损伤的背景下，最终推进治疗 老年痴呆症填补这些知识空白可能会对公共卫生产生持久的影响。而且我们 靶向miR-223的基于miRNA的创新治疗策略为新药的有效性提供了证据 目标人群，特别是女性，易患与神经炎症和ApoE相关疾病 失调，包括阿尔茨海默病和其他脑损伤。

Project Title: MicroRNA lipid-nanoparticle based therapy targets neuroinflammation and ApoE dysregulation in Alzheimer’s disease Abstract MicroRNAs (miRNA) are small non-coding regulatory RNA that have large impacts in health and disease. While prior studies have implicated miRNA in Alzheimer’s disease and associated dementias (ADRD), they have not been used yet in a successful therapeutic strategy. We discovered that microRNA-223 (miR-223), a miRNA residing on the X-chromosome which is enriched in microglia/macrophage cells, regulates a sexually dimorphic ApoE pathway via targeting CCAAT-enhancer-binding protein beta (CEBPβ). CEBPβ is an important regulator of neuroinflammatory response and acts as a transcription factor mediating ApoE expression. Our recent data showed that deficiency of miR-223 resulted in a substantial, female-biased elevation of CEBPβ, ApoE, and a heightened inflammatory state in macrophages and in aged mouse brain following a brain injury. Thus, miR-223 appears to regulate a sexually dimorphic microglia/macrophages-dependent increase in inflammation and ApoE as brain cells become activated in parallel with age, injury, and/or Alzheimer’s disease-related pathology. We further demonstrated that miR-223 can be targeted using a novel miRNA-liposome delivery system. Based on these exciting preliminary results, the main goals of this proposal are to test the miR-223-CEBPβ pathway in regulating inflammation-triggered ApoE dysregulation in the biological context of age, sex, and Alzheimer’s disease-relevant brain injury event; and, to test the efficacy of a novel liposome-miRNA delivery method as a potential therapeutic strategy. To complete these objectives, we will 1) confirm that miR-223 directly targets the CEBPβ-ApoE pathway in myeloid cells, and test whether liposome-miR-223 delivery affects this pathway; 2) test the miR-223-CEBPβ- ApoE pathway using a brain injury mouse model and target the pathway using the liposome miRNA delivery system in a novel miR-223 knockout mouse; 3) evaluate the miR-223-CEBPβ-ApoE pathway in human cells in parallel with neuropathological changes of Alzheimer’s disease. These studies will include assessments of brain tissue from the world-class University of Kentucky Alzheimer’s Disease Center biobank. Completion of the funded studies will extend our understanding of mechanisms regulating inflammation/ApoE pathways in the context of sex, aging, and brain injury, ultimately advancing treatments for Alzheimer’s disease. Filling these knowledge gaps could have a lasting impact on public health. Moreover, our innovative miRNA-based therapeutic strategy targeting miR-223 provides a proof of efficacy for a new drug target, particularly in females, who are vulnerable for diseases associated with neuroinflammation and ApoE dysregulation, including Alzheimer’s disease and other brain injury.