Levi Ofir, Jongen-Relo Ana L, Feldon Joram, Roses Allen D, Michaelson Daniel M
The Department of Neurobiochemistry, The George S. Wise Faculty of Life Sciences, Tel Aviv University, 69978, Ramat Aviv, Israel.
Neurobiol Dis. 2003 Aug;13(3):273-82. doi: 10.1016/s0969-9961(03)00045-7.
Alzheimer's disease (AD) is associated with genetic risk factors, of which the allele E4 of apolipoprotein E (apoE4) is the most prevalent, and is affected by environmental factors that include education early in life and socioeconomic background. The extent to which environmental factors affect the phenotypic expression of the AD genetic risk factors is not known. Here we show that the neuronal and cognitive stimulations, which are elicited by environmental enrichment at a young age, are markedly affected by the apoE genotype. Accordingly, exposure to an enriched environment of young mice transgenic for human apoE3, which is the benign AD apoE allele, resulted in improved learning and memory, whereas mice transgenic for human apoE4 were unaffected by the enriched environment and their learning and memory were similar to those of the nonenriched apoE3 transgenic mice. These cognitive effects were associated with higher hippocampal levels of the presynaptic protein synaptophysin and of NGF in apoE3 but not apoE4 transgenic mice. In contrast, cortical synaptophysin and NGF levels of the apoE3 and apoE4 transgenic mice were similarly elevated by environmental enrichment. These findings show that apoE4 impairs hippocampal plasticity and isoform-specifically blocks the environmental stimulation of synaptogenesis and memory. This provides a novel mechanism by which environmental factors can modulate the function and phenotypic expression of the apoE genotype.
阿尔茨海默病（AD）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，并且受包括早年教育和社会经济背景在内的环境因素影响。环境因素对AD遗传风险因素表型表达的影响程度尚不清楚。在此我们表明，幼年时环境丰富化所引发的神经元和认知刺激，明显受到apoE基因型的影响。相应地，将幼年的人类apoE3转基因小鼠（apoE3是良性的AD apoE等位基因）暴露于丰富环境中，可改善其学习和记忆能力，而人类apoE4转基因小鼠则不受丰富环境的影响，其学习和记忆能力与未处于丰富环境中的apoE3转基因小鼠相似。这些认知效应与apoE3转基因小鼠而非apoE4转基因小鼠海马中突触前蛋白突触素和神经生长因子（NGF）水平升高有关。相比之下，环境丰富化使apoE3和apoE4转基因小鼠皮质中的突触素和NGF水平同样升高。这些发现表明，apoE4损害海马可塑性，并以异构体特异性方式阻断环境对突触形成和记忆的刺激。这提供了一种新机制，通过该机制环境因素可调节apoE基因型的功能和表型表达。
