Kim Jaekwang, Yoon Hyejin, Horie Takahiro, Burchett Jack M, Restivo Jessica L, Rotllan Noemi, Ramírez Cristina M, Verghese Philip B, Ihara Masafumi, Hoe Hyang-Sook, Esau Christine, Fernández-Hernando Carlos, Holtzman David M, Cirrito John R, Ono Koh, Kim Jungsu
Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida 32224, Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University School of Medicine, St. Louis, Missouri 63110.
Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
J Neurosci. 2015 Nov 4;35(44):14717-26. doi: 10.1523/JNEUROSCI.2053-15.2015.
Dysregulation of amyloid-β (Aβ) metabolism is critical for Alzheimer's disease (AD) pathogenesis. Mounting evidence suggests that apolipoprotein E (ApoE) is involved in Aβ metabolism. ATP-binding cassette transporter A1 (ABCA1) is a key regulator of ApoE lipidation, which affects Aβ levels. Therefore, identifying regulatory mechanisms of ABCA1 expression in the brain may provide new therapeutic targets for AD. Here, we demonstrate that microRNA-33 (miR-33) regulates ABCA1 and Aβ levels in the brain. Overexpression of miR-33 impaired cellular cholesterol efflux and dramatically increased extracellular Aβ levels by promoting Aβ secretion and impairing Aβ clearance in neural cells. In contrast, genetic deletion of mir-33 in mice dramatically increased ABCA1 levels and ApoE lipidation, but it decreased endogenous Aβ levels in cortex. Most importantly, pharmacological inhibition of miR-33 via antisense oligonucleotide specifically in the brain markedly decreased Aβ levels in cortex of APP/PS1 mice, representing a potential therapeutic strategy for AD.
Brain lipid metabolism, in particular Apolipoprotein E (ApoE) lipidation, is critical to Aβ metabolism and Alzheimer's disease (AD). Brain lipid metabolism is largely separated from the periphery due to blood-brain barrier and different repertoire of lipoproteins. Therefore, identifying the novel regulatory mechanism of brain lipid metabolism may provide a new therapeutic strategy for AD. Although there have been studies on brain lipid metabolism, its regulation, in particular by microRNAs, is relatively unknown. Here, we demonstrate that inhibition of microRNA-33 increases lipidation of brain ApoE and reduces Aβ levels by inducing ABCA1. We provide a unique approach for AD therapeutics to increase ApoE lipidation and reduce Aβ levels via pharmacological inhibition of microRNA in vivo.
淀粉样蛋白-β（Aβ）代谢失调对阿尔茨海默病（AD）的发病机制至关重要。越来越多的证据表明载脂蛋白E（ApoE）参与Aβ代谢。ATP结合盒转运蛋白A1（ABCA1）是ApoE脂化的关键调节因子，其影响Aβ水平。因此，确定大脑中ABCA1表达的调节机制可能为AD提供新的治疗靶点。在此，我们证明微小RNA-33（miR-33）调节大脑中的ABCA1和Aβ水平。miR-33的过表达损害细胞胆固醇外流，并通过促进神经细胞中Aβ分泌和损害Aβ清除而显著增加细胞外Aβ水平。相反，小鼠中mir-33的基因缺失显著增加ABCA1水平和ApoE脂化，但降低皮质中的内源性Aβ水平。最重要的是，通过反义寡核苷酸在大脑中特异性地对miR-33进行药理学抑制，可显著降低APP/PS1小鼠皮质中的Aβ水平，这代表了一种针对AD的潜在治疗策略。
大脑脂质代谢，尤其是载脂蛋白E（ApoE）脂化，对Aβ代谢和阿尔茨海默病（AD）至关重要。由于血脑屏障和不同的脂蛋白库，大脑脂质代谢在很大程度上与外周不同。因此，确定大脑脂质代谢的新调节机制可能为AD提供新的治疗策略。尽管已有关于大脑脂质代谢的研究，但其调节，尤其是微小RNA的调节，相对未知。在此，我们证明抑制微小RNA-33可增加大脑ApoE的脂化并通过诱导ABCA1降低Aβ水平。我们提供了一种独特的AD治疗方法，即通过体内对微小RNA进行药理学抑制来增加ApoE脂化并降低Aβ水平。
