Rapp Alfred, Gmeiner Bernhard, Hüttinger Manfred
Department of Medical Chemistry, MedUniWien, Center of Physiology and Pathophysiology, Medical University of Vienna, Währingerstrasse 10, 1090 Vienna, Austria.
Biochimie. 2006 May;88(5):473-83. doi: 10.1016/j.biochi.2005.10.007. Epub 2005 Nov 15.
Apolipoprotein E (apoE) has been genetically linked to late-onset Alzheimer's disease. From the three common alleles (epsilon2, epsilon3 and epsilon4), epsilon4 has been suggested to promote amyloid beta (Ass) plaque fibrillation, one hallmark of Alzheimer's disease. It has been demonstrated that altered lipid content of hippocampal plasma membrane coincides with the disease. In this study, we show for the first time that the apoE dependent cholesterol metabolism in hippocampal neurons is higher than that of hippocampal astrocytes. Further, apoE-bound cholesterol is highly incorporated in membranous compartments in hippocampal neurons, whereas hippocampal astrocytes show higher intracellular distribution. This is an effect that coincides with cell-type dependent difference of low density lipoprotein receptor (LDLR) family member expression. Hippocampal neurons express high levels of the LDLR related protein (LRP), whereas hippocampal astrocytes are highly positive for LDLR. We could also demonstrate an apoE isoform (apoE2, apoE3 and apoE4) dependent cholesterol uptake in both cells types. In hippocampal neurons, we could find a decreased apoE4-bound cholesterol uptake. In contrast, hippocampal astrocytes show decreased internalization of apoE2-bound cholesterol. In addition, lipidated apoE4 is little associated with neurites in hippocampal neurons in comparison to the other two isoforms. In contrary, hippocampal astrocytes show faint apoE2 immunocytostaining intensity. Data presented indicate that the role of apoE4 in cholesterol homeostasis and apolipoprotein cell association is more pronounced in hippocampal neurons, showing significant alterations compared to the other two isoforms, suggesting that hippocampal neurons are affected by apoE4 associated altered cholesterol metabolism compared to hippocampal astrocytes.
载脂蛋白E（apoE）在基因上与晚发性阿尔茨海默病相关。在三个常见等位基因（ε2、ε3和ε4）中，ε4被认为会促进β淀粉样蛋白（Aβ）斑块纤维化，这是阿尔茨海默病的一个标志。已经证明，海马质膜脂质含量的改变与该疾病相符。在本研究中，我们首次表明海马神经元中依赖载脂蛋白E的胆固醇代谢高于海马星形胶质细胞。此外，与载脂蛋白E结合的胆固醇高度整合在海马神经元的膜性区室中，而海马星形胶质细胞则表现出更高的细胞内分布。这一效应与低密度脂蛋白受体（LDLR）家族成员表达的细胞类型依赖性差异相符。海马神经元表达高水平的低密度脂蛋白受体相关蛋白（LRP），而海马星形胶质细胞对LDLR呈高度阳性。我们还能够证明两种细胞类型中均存在载脂蛋白E异构体（apoE2、apoE3和apoE4）依赖性胆固醇摄取。在海马神经元中，我们发现与载脂蛋白E4结合的胆固醇摄取减少。相比之下，海马星形胶质细胞中与载脂蛋白E2结合的胆固醇内化减少。此外，与其他两种异构体相比，脂化的载脂蛋白E4与海马神经元中的神经突几乎没有关联。相反，海马星形胶质细胞显示出微弱的载脂蛋白E2免疫细胞化学染色强度。所呈现的数据表明，载脂蛋白E4在胆固醇稳态和载脂蛋白细胞关联中的作用在海马神经元中更为显著，与其他两种异构体相比有显著改变，这表明与海马星形胶质细胞相比，海马神经元受载脂蛋白E4相关的胆固醇代谢改变影响更大。
