Hirsch-Reinshagen Veronica, Maia Luis F, Burgess Braydon L, Blain Jean-Francois, Naus Kathryn E, McIsaac Sean A, Parkinson Pamela F, Chan Jennifer Y, Tansley Gavin H, Hayden Michael R, Poirier Judes, Van Nostrand William, Wellington Cheryl L
Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia V4Z 5H5, Canada.
J Biol Chem. 2005 Dec 30;280(52):43243-56. doi: 10.1074/jbc.M508781200. Epub 2005 Oct 5.
ABCA1, a cholesterol transporter expressed in the brain, has been shown recently to be required to maintain normal apoE levels and lipidation in the central nervous system. In addition, ABCA1 has been reported to modulate beta-amyloid (Abeta) production in vitro. These observations raise the possibility that ABCA1 may play a role in the pathogenesis of Alzheimer disease. Here we report that the deficiency of ABCA1 does not affect soluble or guanidine-extractable Abeta levels in Tg-SwDI/B or amyloid precursor protein/presenilin 1 (APP/PS1) mice, but rather is associated with a dramatic reduction in soluble apoE levels in brain. Although this reduction in apoE was expected to reduce the amyloid burden in vivo, we observed that the parenchymal and vascular amyloid load was increased in Tg-SwDI/B animals and was not diminished in APP/PS1 mice. Furthermore, we observed an increase in the proportion of apoE retained in the insoluble fraction, particularly in the APP/PS1 model. These data suggested that ABCA1-mediated effects on apoE levels and lipidation influenced amyloidogenesis in vivo.
ABCA1是一种在大脑中表达的胆固醇转运蛋白，最近研究表明，它对于维持中枢神经系统中正常的载脂蛋白E（apoE）水平和脂化是必需的。此外，据报道ABCA1在体外可调节β-淀粉样蛋白（Aβ）的产生。这些观察结果增加了ABCA1可能在阿尔茨海默病发病机制中起作用的可能性。在此我们报告，ABCA1的缺乏并不影响Tg-SwDI/B或淀粉样前体蛋白/早老素1（APP/PS1）小鼠中可溶性或胍可提取的Aβ水平，而是与脑中可溶性apoE水平的显著降低有关。尽管预计apoE的这种降低会减轻体内的淀粉样蛋白负担，但我们观察到Tg-SwDI/B动物实质和血管中的淀粉样蛋白负荷增加，而在APP/PS1小鼠中并未减少。此外，我们观察到保留在不溶性部分中的apoE比例增加，特别是在APP/PS1模型中。这些数据表明，ABCA1对apoE水平和脂化的影响在体内影响了淀粉样蛋白的生成。
