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

阿尔茨海默病(AD)是一种毁灭性的神经退行性疾病；现有的治疗方法有限 改善症状。我们的目标是确定导致阿尔茨海默病神经变性的神经生物学机制。 MicroRNAs(MiRNA)是典型的沉默翻译的内源性非编码RNA分子。很少有研究 存在于miRNAs的作用中，这些miRNAs作为神经生物学的参与者，针对与AD有关的基因产物。我们最近 发现了一种miRNA(MiR346)，它能刺激淀粉样蛋白前体蛋白(APP)作为铁的一部分进行翻译 (Fe)动态平衡。这种miRNA结合了一个与APP中的铁反应元件(IRE)重叠的站点。MiR346也 在tau 3‘-非编码区有一个预测的位点，tau促进了铁稳态中APP的活性。此外，我们已经确定了 MiR298降低APP和特定tau蛋白部分的水平。提案的目标是测试“平衡” 在miR346、miR298、Fe和细胞炎症网络中通过APP和tau(Feat)。我们的中央- 假设1)miR346在维持铁的动态平衡方面起着至关重要的作用；2)操纵miRNA可以改变铁的方向 新陈代谢以预防或治疗AD和其他神经退行性疾病。 SA1：检验假设-miR346和298与APP和tau mRNA非翻译区(UTR)相互作用 奎恩斯。理论基础：铁代谢紊乱与AD有关。APP和tau在铁代谢中起作用。A联席- 两者的调节也参与了铁的代谢，可能是预防AD相关神经毒性的重要工具。 城市。影响：研究表明miR346和miR298共同调节APP和tau。 SA2：miR346和298对APP和tau的调节均导致铁代谢紊乱并对其作出反应。 理论基础：我们打算在铁代谢中建立miR346和miR298活性的特定机制。 MiR298将间接参与铁水平的反应。识别miRNA介导的调控作用 在这个网络中，应该阐明miRNA依赖的药理操纵机制。影响： 这些研究可能揭示miRNA功能和Feat Trio调控的新的生物学机制。 SA3：检验假设-miR346和298在AD分期和脑区域特异性人中调节失调- 内斯。理论基础：我们将在具有良好特征的临床样本中确定Feat与miR346和miR298的合作伙伴 普莱斯。我们预计，监管将在解剖学和病理学依赖的模式上有所不同。影响：这些研究在 AD患者将进一步确立miRNAs作为治疗靶点。 SA4：翻译miR346和miR298对铁稳态、APP和tau的操纵，以及关键的促进 转基因阿尔茨海默病模型小鼠体内的酶活性。理论基础：我们打算确定AD病理是如何或是否 影响相互作用以及这种相互作用如何影响AD病理。我们将特别注意差异 在野生型和转基因小鼠中对miRNAs或阻断的反应。影响：确定如何操纵 在正常和诱导的病理系统中，miR346都会改变相关的蛋白质水平，着眼于 通过miR346对照减少病理改变。

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.