Role of microRNA-33 in Alzheimer's disease

项目概要/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 功能的调节已经产生了有希望的临床数据 对于多种疾病，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 亚型外， ApoE 水平和脂化状态的改变已被证明会影响 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 AD 发病机制中发挥关键作用。因此，针对炎症通路是一种新兴的治疗方法 策略，以及直接靶向 ApoE/Aβ 通路，用于 AD 治疗。最近，我们发现miR-33 基因缺失显着增加 ABCA1 水平和可溶性 Aβ 清除率，导致可溶性 Aβ 减少 APP/PS1 小鼠模型大脑中的 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 (TGFβ) 受体 1 (TGFβR1) 基因。在这里，我们现在寻求 定义 miR-33 在小鼠 ApoE 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 敲除和 ApoE 敲除小鼠以及 miR-33 敲除小鼠 模型。在目标 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 基于寡核苷酸 (ASO) 的 miR-33 药理抑制有效提高 ABCA1 水平 降低大脑中可溶性 Aβ 的水平。在目标 3 中，我们将评估抗 miR-33 长期治疗的效果 ASO 对 Aβ 沉积、神经炎症和小鼠行为的影响。我们将评估预防和 在 Aβ 斑块和记忆形成之前和之后治疗抗 miR-33 ASO 的治疗效果 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.