Stukas Sophie, May Sharon, Wilkinson Anna, Chan Jeniffer, Donkin James, Wellington Cheryl L
Department of Pathology and Laboratory Medicine, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada V5Z 4H4.
Biochim Biophys Acta. 2012 Mar;1821(3):536-46. doi: 10.1016/j.bbalip.2011.08.014. Epub 2011 Aug 26.
Lipoprotein metabolism in the central nervous system (CNS) is based on high-density lipoprotein-like particles that use apoE as their predominant apolipoprotein rather than apoA-I. Although apoA-I is not expressed in astrocytes and microglia, which produce CNS apoE, apoA-I is reported to be expressed in porcine brain capillary endothelial cells and also crosses the blood-brain barrier (BBB). These mechanisms allow apoA-I to reach concentrations in cerebrospinal fluid (CSF) that are approximately 0.5% of its plasma levels. Recently, apoA-I has been shown to enhance cognitive function and reduce cerebrovascular amyloid deposition in Alzheimer's Disease (AD) mice, raising questions about the regulation and function of apoA-I in the CNS. Peripheral apoA-I metabolism is highly influenced by ABCA1, but less is known about how ABCA1 regulates CNS apoA-I. We report that ABCA1 deficiency leads to greater retention of apoA-I in the CNS than in the periphery. Additionally, treatment of symptomatic AD mice with GW3965, an LXR agonist that stimulates ABCA1 expression, increases apoA-I more dramatically in the CNS compared to the periphery. Furthermore, GW3965-mediated up-regulation of CNS apoA-I is independent of ABCA1. Our results suggest that apoA-I may be regulated by distinct mechanisms on either side of the BBB and that apoA-I may serve to integrate peripheral and CNS lipid metabolism. This article is part of a Special Issue entitled Advances in High Density Lipoprotein Formation and Metabolism: A Tribute to John F. Oram (1945-2010).
中枢神经系统（CNS）中的脂蛋白代谢基于以载脂蛋白E（apoE）而非载脂蛋白A-I（apoA-I）作为主要载脂蛋白的高密度脂蛋白样颗粒。尽管产生中枢神经系统apoE的星形胶质细胞和小胶质细胞中不表达apoA-I，但据报道apoA-I在猪脑毛细血管内皮细胞中表达，并且还能穿过血脑屏障（BBB）。这些机制使apoA-I在脑脊液（CSF）中的浓度达到其血浆水平的约0.5%。最近，已证明apoA-I可增强阿尔茨海默病（AD）小鼠的认知功能并减少脑血管淀粉样蛋白沉积，这引发了关于apoA-I在中枢神经系统中的调节和功能的问题。外周apoA-I代谢受ATP结合盒转运体A1（ABCA1）的高度影响，但关于ABCA1如何调节中枢神经系统apoA-I的了解较少。我们报告称，ABCA1缺乏导致apoA-I在中枢神经系统中的潴留比在外周更严重。此外，用GW3965（一种刺激ABCA1表达的肝脏X受体（LXR）激动剂）治疗有症状的AD小鼠，与外周相比，中枢神经系统中apoA-I的增加更为显著。此外，GW3965介导的中枢神经系统apoA-I上调与ABCA1无关。我们的结果表明，apoA-I可能在血脑屏障两侧受到不同机制的调节，并且apoA-I可能有助于整合外周和中枢脂质代谢。本文是名为“高密度脂蛋白形成与代谢进展：向约翰·F·奥拉姆致敬（1945 - 2010）”的特刊的一部分。
