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， 神经退行性疾病尽管miRNA功能的调节已经产生了有希望的临床数据， 对于几种疾病，miRNA在阿尔茨海默病（AD）中的作用尚未得到彻底研究。 载脂蛋白E（ApoE）基因型是AD最强的遗传危险因素。除了ApoE同种型， ApoE水平和脂化状态的改变已显示影响Aβ聚集。我们和其他人 报道了ATP结合盒转运蛋白A1（ABCA 1）在调节ApoE脂化和Aβ 以及它的治疗潜力。越来越多的证据表明，神经炎症起着重要作用。 在AD发病机制中的关键作用。因此，靶向炎症通路是一种新兴的治疗方法 沿着直接靶向ApoE/Aβ通路的治疗策略。最近，我们发现miR-33 基因缺失显著增加ABCA 1水平和可溶性Aβ清除，导致可溶性A β减少。 APP/PS1小鼠模型脑内Aβ水平。我们还发现miR-33调节神经炎症， 直接靶向转化生长因子β受体1（TGFβR1）基因。在这里，我们现在寻求 明确miR-33在小鼠ApoE和β淀粉样蛋白（Aβ）代谢（Aim 1）以及神经炎症（Aim 2）的情况。在目标1中，我们将使用ABCA 1敲除和ApoE敲除小鼠连同miR-33敲除小鼠沿着。 模型目的2：建立TGFβR1基因敲除小鼠模型。重要的是，我们证明了反义 基于寡核苷酸（阿索）的miR-33的药理学抑制有效地增加ABCA 1水平， 降低大脑中可溶性Aβ水平。在目标3中，我们将评估抗miR-33长期治疗的效果。 阿索对小鼠Aβ沉积、神经炎症和行为的影响。我们将评估预防和 在Aβ斑块和记忆发展前后治疗抗miR-33阿索的治疗效果 APP/PS1小鼠中的缺陷。