Bimonte-Nelson Heather A, Singleton Rachel S, Nelson Matthew E, Eckman Christopher B, Barber John, Scott Tonetta Y, Granholm Ann-Charlotte E
Department of Physiology and Neuroscience and the Center for Studies on Aging, Medical University of South Carolina, Charleston 29425, USA.
Exp Neurol. 2003 Jun;181(2):301-12. doi: 10.1016/s0014-4886(03)00061-x.
Recent studies have suggested that testosterone levels are lower in men with Alzheimer's disease and that testosterone treatment improves cognition in older men. Since testosterone can be aromatized to estrogen, testosterone's effects could be due to conversion into estrogen. We treated aged male rats with either testosterone or dihydrotestosterone (DHT), the latter of which is not aromatized to estrogen, in order to determine whether these treatments improve spatial working and reference memory as assessed in the water radial arm maze. We also tested whether such effects are related to beta-amyloid levels in the hippocampus or neurotrophin levels in the hippocampus, entorhinal cortex, frontal cortex, or striatum. Aged rats made more errors than young rats on all memory measures. Testosterone, but not DHT, improved working memory and decreased hippocampal NGF protein in aged rats, while having no effect on beta-amyloid. However, higher beta-amyloid levels were correlated with poorer working memory performance in young rats. Neurotrophin levels in entorhinal cortex were positively correlated with errors for all memory measures in androgen-treated rats. Similar to findings in human studies, in our study androgen treatment lowered circulating estradiol levels in aged rats, suggesting that androgen treatment exerts feedback to the hypothalamic pituitary axis and that conversion to estrogen may not be the underlying biological mechanism of testosterone's effects on memory and growth factor levels. The ratio of estradiol to testosterone, or the actions of the aromatase enzyme itself, may be responsible for the observed effects. These data support the hypothesis that testosterone therapy in aging men may provide positive effects on cognition and that neural regions that are linked to cognition, such as the hippocampus and/or entorhinal cortex, may be involved in such effects.
近期研究表明，阿尔茨海默病男性患者的睾酮水平较低，且睾酮治疗可改善老年男性的认知能力。由于睾酮可芳香化转化为雌激素，睾酮的作用可能归因于其转化为雌激素。我们用睾酮或双氢睾酮（DHT）处理老年雄性大鼠，后者不能芳香化转化为雌激素，以确定这些处理是否能改善在水迷宫中评估的空间工作记忆和参考记忆。我们还测试了这些作用是否与海马体中的β-淀粉样蛋白水平或海马体、内嗅皮质、额叶皮质或纹状体中的神经营养因子水平有关。在所有记忆测试中，老年大鼠比年轻大鼠犯的错误更多。睾酮而非双氢睾酮改善了老年大鼠的工作记忆并降低了海马体中的NGF蛋白水平，同时对β-淀粉样蛋白没有影响。然而，在年轻大鼠中，较高的β-淀粉样蛋白水平与较差的工作记忆表现相关。在雄激素处理的大鼠中，内嗅皮质中的神经营养因子水平与所有记忆测试中的错误呈正相关。与人体研究结果相似，在我们的研究中，雄激素处理降低了老年大鼠的循环雌二醇水平，这表明雄激素处理对下丘脑-垂体轴产生反馈作用，且转化为雌激素可能不是睾酮对记忆和生长因子水平产生作用的潜在生物学机制。雌二醇与睾酮的比例，或芳香化酶本身的作用，可能是观察到的这些作用的原因。这些数据支持这样一种假设，即老年男性的睾酮治疗可能对认知产生积极影响，且与认知相关的神经区域，如海马体和/或内嗅皮质，可能参与了这种影响。
