Role of microRNA-33 in Alzheimer's disease

microRNA-33 在阿尔茨海默病中的作用

• 批准号: 9338097
• 负责人: Jungsu Kim
• 金额: $ 39.35万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9338097
• 关键词: APP-PS1; ATP-Binding Cassette Transporters; Abeta clearance; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid beta-Protein; Anti-Inflammatory Agents; Anti-inflammatory; Antisense Oligonucleotides; Apolipoprotein A-I; Apolipoprotein E; Attention; Behavior; Brain; Budgets; Bypass; Cardiovascular Diseases; Cholesterol; Clinical; Clinical Data; Cognition; Combined Modality Therapy; Complement Factor B; Complex; Data; Development; Disease; Gene Deletion; Genes; Genetic; Genotype; Impairment; In Vitro; Inflammatory; Inflammatory Response; Knock-out; Knockout Mice; Lipids; Lipoproteins; Long-Term Effects; Measurement; Memory; Memory Loss; Memory impairment; Mental disorders; Metabolism; Methodology; MicroRNAs; Microglia; Molecular; Molecular Genetics; Mus; Neurodegenerative Disorders; Neurons; Neurosciences; Pathogenesis; Pathogenicity; Pathologic; Pathway interactions; Pharmacology; Play; Preventive; Process; Protein Isoforms; Proteins; Reporting; Research Priority; Role; Senile Plaques; Signal Transduction; Systems Biology; Testing; Therapeutic; Therapeutic Effect; Transforming Growth Factor beta; Transforming Growth Factor beta Receptors; Transforming Growth Factors; Translating; Treatment Efficacy; Untranslated RNA; abeta accumulation; abeta deposition; base; cell type; disease phenotype; genetic approach; genetic risk factor; improved; in vivo; innovation; insight; lipid metabolism; metabolic rate; mouse model; neuroinflammation; novel; protein aggregation; receptor; targeted treatment; therapeutic target

PROJECT SUMMARY/ABSTRACT Mounting evidence suggests that microRNA (miRNA) dysregulation may contribute to psychiatric disorders and neurodegenerative disorders. Although modulations of miRNA function have generated promising clinical data for several diseases, miRNA’s role in Alzheimer’s disease (AD) has not been investigated thoroughly. Apolipoprotein E (ApoE) genotype is the strongest genetic risk factor for AD. In addition to ApoE isoform, alterations in ApoE levels and lipidation status have been shown to influence Aβ aggregation. We and others reported the critical roles of ATP-binding cassette transporter A1 (ABCA1) in regulating ApoE lipidation and Aβ levels in the brain and its therapeutic potential. Increasing evidence suggests that neuroinflammation plays a critical role in AD pathogenesis. Therefore, targeting inflammatory pathways is an emerging therapeutic strategy, along with the direct targeting of ApoE/Aβ pathway, for AD therapy. Recently, we found that miR-33 gene deletion significantly increases ABCA1 levels and soluble Aβ clearance, leading to reduction of soluble Aβ levels in the brain of APP/PS1 mouse model. We also identified that miR-33 regulates neuroinflammation by directly targeting transforming growth factor β (TGFβ) receptor 1 (TGFβR1) gene. Here, we now seek to define the role of miR-33 in ApoE and Amyloid β (Aβ) metabolism in mice (Aim 1) and neuroinflammation (Aim 2). In Aim 1, we will use ABCA1 knockout and ApoE knockout mice along with miR-33 knockout mouse models. In Aim 2, we will use TGFβR1 knockout mouse model. Importantly, we demonstrated that antisense oligonucleotide (ASO)-based pharmacological inhibition of miR-33 efficiently increases ABCA1 levels and reduces soluble Aβ levels in the brain. In Aim 3, we will assess the effect of long-term treatment of anti-miR-33 ASO on Aβ deposition, neuroinflammation, and behavior in mice. We will assess the preventive and therapeutic effect by treating anti-miR-33 ASO before and after the development of Aβ plaques and memory deficits in APP/PS1 mice.

项目摘要/摘要 越来越多的证据表明，microRNA（miRNA）失调可能导致精神疾病和 神经退行性疾病。尽管miRNA功能的调制已经产生了有希望的临床数据 对于几种疾病，米尔纳在阿尔茨海默氏病（AD）中的作用尚未得到彻底研究。 载脂蛋白E（APOE）基因型是AD的强遗传风险因素。除了apoe同工型， APOE水平的改变和脂化状态已显示会影响Aβ聚集。我们和其他人 报道了ATP结合盒转运蛋白A1（ABCA1）在调节APOE脂质和Aβ中的关键作用 大脑的水平及其治疗潜力。越来越多的证据表明神经炎症起着 在AD发病机理中的关键作用。因此，靶向炎症途径是一种新兴疗法 策略以及APOE/Aβ途径的直接靶向AD疗法。最近，我们发现mir-33 基因缺失显着增加了ABCA1水平和可溶性Aβ清除率，导致可溶性降低 APP/PS1小鼠模型大脑中的Aβ水平。我们还确定miR-33调节神经炎症 通过直接靶向转化生长因子β（TGFβ）受体1（TGFβR1）基因。在这里，我们现在寻求 定义miR-33在APOE和淀粉样β（Aβ）代谢中的作用（AIM 1）和神经炎症（AIM 2）。在AIM 1中，我们将使用ABCA1淘汰赛和APOE淘汰小鼠以及miR-33淘汰鼠标 型号。在AIM 2中，我们将使用TGFβR1敲除小鼠模型。重要的是，我们证明了反义 miR-33的基于寡核苷酸（ASO）的药物抑制有效地增加了ABCA1水平和 降低大脑中的固体Aβ水平。在AIM 3中，我们将评估抗MIR-33的长期治疗的影响 Aβ沉积，神经炎症和小鼠行为的ASO。我们将评估预防性和 通过治疗Aβ斑块和记忆前后治疗抗MIR-33 ASO的治疗效果 APP/PS1小鼠的缺陷。