Levi Ofir, Michaelson Daniel M
Department of Neurobiochemistry, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
J Neurochem. 2007 Jan;100(1):202-10. doi: 10.1111/j.1471-4159.2006.04189.x. Epub 2006 Oct 27.
Neurodegeneration in Alzheimer's disease (AD) is associated with the activation of neurogenesis. The mechanisms underlying this crosstalk between neuronal death and birth and the extent to which it is affected by genetic risk factors of AD are not known. We employed transgenic mice expressing human apolipoprotein E4 (apoE4), the most prevalent genetic risk factor for AD, or expressing human apoE3 (an AD-benign allele), in order to examine the hypothesis that apoE4 tilts the balance between neurogenesis and neuronal cell death in favor of the latter. The results showed an isoform-specific increase in neurogenesis in the hippocampal dentate gyrus (DG) under standard conditions in apoE4-transgenic mice. Environmental stimulation, which increases neurogenesis in the DG of apoE3-transgenic and wild-type mice, had the opposite effect on the apoE4 mice, where it triggered apoptosis while decreasing hippocampal neurogenesis. These effects were specific to the DG and were not observed in the subventricular zone, where neurogenesis was unaffected by either the apoE genotype or the environmental conditions. These in vivo findings demonstrate a linkage between neuronal apoptosis and the impaired neuronal plasticity and cognition of apoE4-transgenic mice, and suggest that similar interactions between apoE4 and environmental factors might occur in AD.
阿尔茨海默病（AD）中的神经退行性变与神经发生的激活有关。神经元死亡与新生之间这种相互作用的潜在机制以及它受AD遗传风险因素影响的程度尚不清楚。我们使用了表达人类载脂蛋白E4（apoE4，AD最常见的遗传风险因素）或表达人类apoE3（一种对AD无害的等位基因）的转基因小鼠，以检验apoE4使神经发生与神经元细胞死亡之间的平衡向有利于后者倾斜这一假设。结果显示，在标准条件下，apoE4转基因小鼠海马齿状回（DG）中的神经发生呈异构体特异性增加。环境刺激可增加apoE3转基因小鼠和野生型小鼠DG中的神经发生，但对apoE4小鼠却产生相反的作用，它在apoE4小鼠中引发凋亡，同时减少海马神经发生。这些效应是DG特有的，在脑室下区未观察到，在该区域神经发生不受apoE基因型或环境条件的影响。这些体内研究结果证明了神经元凋亡与apoE4转基因小鼠神经元可塑性受损及认知障碍之间的联系，并表明apoE4与环境因素之间可能在AD中发生类似的相互作用。
