Nathan Britto P, Barsukova Anna G, Shen Fei, McAsey Mary, Struble Robert G
Department of Biological Sciences, Eastern Illinois University, Charleston, Illinois 61920, USA.
Endocrinology. 2004 Jul;145(7):3065-73. doi: 10.1210/en.2003-1707. Epub 2004 Mar 19.
Literature review suggests a close relationship between estrogen and apolipoprotein E (ApoE) in the central nervous system. Epidemiology studies show that estrogen replacement therapy (ERT) decreases the morbidity from several chronic neurological diseases. Alleles of ApoE modify the risk for and progression of the same diseases. ApoE levels in the rodent brain vary during the estrous cycle and increase after 17beta-estradiol administration. Both estradiol and ApoE3, the most common isoform of human ApoE, increase the extent of neurite outgrowth in culture. Combined, these observations suggest a common mechanism whereby estrogen may increase ApoE levels to facilitate neurite growth. We tested this hypothesis by characterizing the effects of estradiol and ApoE isoforms on neurite outgrowth in cultured adult mouse cortical neurons. Estradiol increased ApoE levels and neurite outgrowth. ApoE2 increased neurite length more so than ApoE3 in the presence of estradiol. Estradiol had no effect on neurite outgrowth from mice lacking the ApoE gene or when only ApoE4, the isoform of ApoE that is associated with increased risk of neurological disease, was exogenously supplied. Cultures from mice transgenic for human ApoE3 or ApoE4 showed the same isoform-specific effect. Neuronal internalization of recombinant human ApoE3 was greater than ApoE4, and ApoE3 was more effective than ApoE4 in facilitating neuronal uptake of a fatty acid. We conclude that estradiol facilitates neurite growth through an ApoE-dependent mechanism. The effects of ERT on chronic neurological diseases may vary with ApoE genotype. The clinical use of ERT may require ApoE genotyping for optimal efficacy.
文献综述表明，雌激素与中枢神经系统中的载脂蛋白E（ApoE）之间存在密切关系。流行病学研究表明，雌激素替代疗法（ERT）可降低多种慢性神经疾病的发病率。ApoE的等位基因会改变这些疾病的风险和进展。啮齿动物大脑中的ApoE水平在发情周期中会发生变化，在给予17β-雌二醇后会升高。雌二醇和人类ApoE最常见的异构体ApoE3，均可增加培养物中神经突生长的程度。综合这些观察结果表明，雌激素可能通过一种共同机制来增加ApoE水平以促进神经突生长。我们通过表征雌二醇和ApoE异构体对培养的成年小鼠皮质神经元神经突生长的影响来验证这一假设。雌二醇增加了ApoE水平和神经突生长。在存在雌二醇的情况下，ApoE2比ApoE3更能增加神经突长度。对于缺乏ApoE基因的小鼠，或者仅外源性提供与神经疾病风险增加相关的ApoE异构体ApoE4时，雌二醇对神经突生长没有影响。转染了人类ApoE3或ApoE4的小鼠培养物表现出相同的异构体特异性效应。重组人ApoE3的神经元内化作用大于ApoE4，并且在促进神经元摄取脂肪酸方面，ApoE3比ApoE4更有效。我们得出结论，雌二醇通过一种依赖ApoE的机制促进神经突生长。ERT对慢性神经疾病的影响可能因ApoE基因型而异。ERT的临床应用可能需要进行ApoE基因分型以获得最佳疗效。
