Role of microRNA-33 in Alzheimer's disease

项目摘要/摘要 越来越多的证据表明，microRNA(MiRNA)调节失调可能导致精神障碍和 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)中的作用还没有得到彻底的研究。 载脂蛋白E(ApoE)基因是阿尔茨海默病最强的遗传危险因素。除了ApoE亚型外， 载脂蛋白E水平和脂化状态的改变已被证明影响Aβ聚集。我们和其他人 报道了三磷酸腺苷结合盒转运体A1在调节载脂蛋白E脂化和Aβ中的关键作用 大脑中的水平及其治疗潜力。越来越多的证据表明，神经炎症在 在阿尔茨海默病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。 策略，结合直接靶向载脂蛋白E/Aβ通路，用于AD治疗。最近，我们发现miR-33 基因缺失显著增加ABCA1水平和可溶性A-β清除率，导致可溶性 APP/PS1小鼠模型脑内Aβ水平。我们还发现miR-33调节神经炎症。 通过直接靶向转化生长因子β(转化生长因子β)受体1(转化生长因子βR1)基因。在这里，我们现在寻求 明确miR-33在小鼠载脂蛋白E和淀粉样蛋白β(Aβ)代谢(AIM 1)和神经炎症(AIM)中的作用 2)。在目标1中，我们将使用ABCA1和ApoE基因敲除小鼠以及miR-33基因敲除小鼠 模特们。在目标2中，我们将使用转化生长因子βR1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(ASO)的miR-33药物抑制有效地增加ABCA1水平和 降低大脑中的可溶性A-β水平。在目标3中，我们将评估长期治疗抗miR-33的效果。 ASO对小鼠β沉积、神经炎症和行为的影响。我们将评估预防性和 抗MIR-33ASO对A-β斑块形成前后及记忆的治疗作用 APP/PS1小鼠的缺陷。

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.