Levi Ofir, Lütjohann Dieter, Devir Aliza, von Bergmann Klaus, Hartmann Tobias, Michaelson Daniel M
Department of Neurobiochemistry, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
J Neurochem. 2005 Nov;95(4):987-97. doi: 10.1111/j.1471-4159.2005.03441.x. Epub 2005 Sep 29.
Alzheimer's disease is associated with genetic risk factors, of which the allele E4 of apolipoprotein E (apoE4) is the most prevalent, and it is also affected by environmental factors such as early life education. We have recently shown, utilizing apoE-deficient and apoE transgenic mice, that synaptogenesis in the hippocampus following environmental stimulation is affected by apoE. In view of the pivotal role of cholesterol in synaptic plasticity, and of its suggested role in synaptogenesis, we presently examined the effects of apoE and environmental stimulation on brain cholesterol homeostasis. The hippocampal levels of cholesterol and its precursors and metabolites in control mice were not affected by exposure to environmental stimulation. In contrast, the hippocampal levels of cholesterol and its precursors lathosterol and desmosterol and metabolite 24S-hydroxycholesterol were lower in apoE-deficient mice that were maintained in a regular environmental than those of corresponding control mice, whereas they were markedly elevated following environmental stimulation. Histological and immunohistochemical experiments revealed that the combined stimulatory effects of apoE deficiency and environmental stimulation on cholesterol metabolism were associated with marked activation of hippocampal astrocytes and with the abnormal accumulation of cholesterol in neurons and astrocytes. These effects were rescued similarly in apoE3 and apoE4 transgenic mice. These findings suggest that apoE plays an important role in the translocation of cholesterol from astrocytes to neurons in vivo and in the regulation and homeostasis of this process.
阿尔茨海默病与遗传风险因素相关，其中载脂蛋白E（apoE）的E4等位基因最为常见，它还受到诸如早期生活教育等环境因素的影响。我们最近利用apoE基因缺陷型和apoE转基因小鼠表明，环境刺激后海马体中的突触形成受apoE影响。鉴于胆固醇在突触可塑性中的关键作用及其在突触形成中的潜在作用，我们目前研究了apoE和环境刺激对脑胆固醇稳态的影响。对照小鼠海马体中胆固醇及其前体和代谢产物的水平不受环境刺激的影响。相反，饲养在常规环境中的apoE基因缺陷型小鼠海马体中胆固醇及其前体羊毛甾醇和链甾醇以及代谢产物24S-羟基胆固醇的水平低于相应对照小鼠，而在环境刺激后它们显著升高。组织学和免疫组织化学实验表明，apoE缺乏和环境刺激对胆固醇代谢的联合刺激作用与海马星形胶质细胞的显著激活以及神经元和星形胶质细胞中胆固醇的异常积累有关。在apoE3和apoE4转基因小鼠中同样观察到这些效应得到挽救。这些发现表明，apoE在体内胆固醇从星形胶质细胞向神经元的转运以及该过程的调节和稳态中起重要作用。
