Role of microRNA in regulating Fe, Amyloid, and Tau (FeAT) in Alzheimer's disease

阿尔茨海默病（AD）是一种破坏性的神经退行性疾病;现有的治疗方法仅限于温和的治疗 改善症状。我们的目标是确定导致AD神经退行性变的神经生物学机制。 microRNA（miRNA）是内源性非编码RNA分子，通常沉默翻译。点研究 存在于作为神经生物学参与者的靶向与AD有关的基因产物的miRNA的作用上。我们最近 发现了一种miRNA（miR 346），它刺激淀粉样β前体蛋白（APP）作为铁的一部分的翻译。 (Fe)体内平衡该miRNA结合与APP中的铁响应元件（IRE）重叠的位点。 在tau 3 '-UTR中具有预测位点，并且tau促进Fe稳态中的APP活性。另外，我们已经确定 miR 298降低APP和特异性tau蛋白部分的水平。建议的目的是测试“平衡 在miR 346、miR 298、Fe和细胞炎症网络之间通过APP和tau（FeAT）的“feat”。我们的中央卫生- 假设1）miR 346在维持Fe稳态中起重要作用; 2）操纵miRNA可以重定向Fe 用于预防或治疗AD和其他神经退行性疾病的药物组合物。 SA 1：检验假设-miR 346和298与APP和tau mRNA非翻译区（UTR）相互作用。 序列。原理：铁稳态异常与AD有关。APP和tau蛋白在铁代谢中起重要作用。一个共同的- 两者的调节因子也参与铁代谢，可能是预防AD相关神经毒性的重要工具。 市影响：研究表明miR 346和miR 298共同调节APP和tau。 SA 2：miR 346和298对APP和tau的调节均导致并响应于Fe稳态失调。 基本原理：我们打算在铁代谢中建立miR 346和miR 298活性的特定机制。 miR 298将间接参与对Fe水平的响应。确定miRNA介导的调节作用 在这个网络中，应该阐明药物操纵的miRNA依赖机制。影响： 这些研究可能揭示miRNA功能和FeAT三重调控的新生物学机制。 SA 3：检验假设-miR 346和298在AD中在阶段和脑区域特异性人中失调- 纳斯理由：我们将在充分表征的临床样品中鉴定FeAT与miR 346和miR 298的合作伙伴。 请。我们预期调控会因解剖学和病理学而异。影响：这些研究 AD患者将进一步确立miRNAs作为治疗靶点。 SA 4：翻译miR 346和miR 298对Fe稳态、APP和tau蛋白以及关键蛋白的操纵。 在转基因AD模型小鼠中的切割酶。理由：我们打算确定AD病理学如何或是否 影响相互作用以及相互作用如何影响AD病理学。我们将特别注意分歧 在野生型与转基因小鼠中响应于miRNA或阻断。影响：确定如何操纵 正常和诱导病理系统中的miR 346将改变相关的蛋白水平， 通过miR 346对照减少病理学。

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder; available therapies only modestly improve symptoms. Our goal is to identify neurobiological mechanisms leading to neurodegeneration in AD. MicroRNAs (miRNA) are endogenous noncoding RNA molecules that typically silence translation. Little research exists on roles of miRNAs that target gene products implicated in AD as participants in neurobiology. We recently discovered a miRNA (miR346) that stimulates translation of amyloid-β precursor protein (APP) as part of iron (Fe) homeostasis. This miRNA binds a site that overlaps an iron responsive element (IRE) in APP. miR346 also has a predicted site in the tau 3’-UTR, and tau facilitates APP activity in Fe homeostasis. Also, we have identified miR298 reducing levels of APP and a specific tau protein moiety. The proposal objective is to test “balancing feat” among miR346, miR298, Fe, and cellular inflammation networks via APP and tau (FeAT). Our central hy- pothesis is 1) miR346 plays a vital role in maintaining Fe homeostasis; 2) Manipulating miRNA could redirect Fe metabolism to prevent or treat AD and other neurodegenerative disorders. SA1: Test hypothesis—miR346 and 298 interact with APP and tau mRNA untranslated region (UTR) se- quences. Rationale: Fe dyshomeostasis is implicated in AD. APP and tau play roles in Fe metabolism. A co- regulator of both that also takes part in Fe metabolism could be a vital tool for preventing AD-related neurotoxi- city. Impact: Studies reveal miR346 and miR298 coregulate APP and tau. SA2: miR346 and 298 regulation of APP and tau both leads to and responds to Fe dyshomeostasis. Rationale: We intend to establish specific mechanisms of miR346 and miR298 activity within Fe metabolism. miR298 will be indirectly involved in response to Fe levels. Identifying the role of miRNA-mediated regulation within this network should elucidate miRNA-dependent mechanisms for pharmacological manipulation. Impact: These studies are likely to reveal novel biological mechanisms for miRNA function and FeAT trio regulation. SA3: Test hypothesis—miR346 and 298 are dysregulated in AD in stage and brain region specific man- ners. Rationale: We will identify partners of FeAT with miR346 and miR298 in well-characterized clinical sam- ples. We expect regulation to vary in anatomical- and pathology-dependent patterns. Impact: These studies in AD patients will further establish the miRNAs as therapeutic targets. SA4: Translate miR346 and miR298 manipulation on Fe homeostasis, APP and tau, and critical pro- cessing enzymes in transgenic AD model mice. Rationale: We intend to ascertain how or if AD pathology affects the interaction and how the interaction affects AD pathology. We will pay particular attention to differences in response to miRNAs or blockade in wild type vs. transgenic mice. Impact: Determining how manipulation of miR346 in both normal and induced pathology systems will alter pertinent protein levels with an eye toward reducing pathology via miR346 control.