Decreases in testosterone and 17β-oestradiol (E(2)) are associated with an increased risk for Alzheimer's disease (AD), which has been attributed to an increase in β-amyloid and tau pathological lesions. Although recent studies have used transgenic animal models to test the effects of sex steroid manipulations on AD-like pathology, almost none have systematically characterised the associations between AD lesions and sex steroid levels in the blood or brain in any mutant model. The present study evaluated age-related changes in testosterone and E(2) concentrations, as well as androgen receptor (AR) and oestrogen receptor (ER) α and β expression, in brain regions displaying AD pathology in intact male and female 3xTgAD and nontransgenic (ntg) mice. We report for the first time that circulating and brain testosterone levels significantly increase in male 3xTgAD mice with age, but without changes in AR-immunoreactive (IR) cell number in the hippocampal CA1 or medial amygdala. The age-related increase in hippocampal testosterone levels correlated positively with increases in the conformational tau isoform, Alz50. These data suggest that the over-expression of human tau up-regulate the hypothalamic-pituitary-gonadal axis in these mice. Although circulating and brain E(2) levels remained stable with age in both male and female 3xTgAD and ntg mice, ER-IR cell number in the hippocampus and medial amygdala decreased with age in female transgenic mice. Furthermore, E(2) levels were significantly higher in the hippocampus than in serum, suggesting local production of E(2). Although triple transgenic mice mimic AD-like pathology, they do not fully replicate changes in human sex steroid levels, and may not be the best model for studying the effects of sex steroids on AD lesions.

译文

睾丸激素和17β-雌二醇 (E(2)) 的减少与阿尔茨海默氏病 (AD) 的风险增加有关,这归因于 β-淀粉样蛋白和tau病理病变的增加。尽管最近的研究已经使用转基因动物模型来测试性类固醇操作对AD样病理的影响,但几乎没有人系统地表征任何突变模型中AD病变与血液或大脑中性类固醇水平之间的关联。本研究评估了在完整的雄性和雌性3xTgAD和非转基因 (ntg) 小鼠中显示AD病理的大脑区域中,睾丸激素和E(2) 浓度以及雄激素受体 (AR) 和雌激素受体 (ER) α 和 β 表达的年龄相关变化。我们首次报道,随着年龄的增长,雄性3xtgad小鼠的循环和脑睾丸激素水平显着增加,但海马CA1或内侧杏仁核中AR免疫反应性 (IR) 细胞数量没有变化。与年龄相关的海马睾丸激素水平的增加与构象tau亚型alz50的增加呈正相关。这些数据表明,人tau的过表达上调了这些小鼠的下丘脑-垂体-性腺轴。尽管雄性和雌性3xtgad和ntg小鼠的循环和脑E(2) 水平随年龄而保持稳定,但雌性转基因小鼠的海马和内侧杏仁核中的ER-IR细胞数量随年龄而降低。此外,海马中的E(2) 水平显着高于血清,表明E(2) 的局部产生。尽管三重转基因小鼠模仿AD样病理,但它们不能完全复制人类性别类固醇水平的变化,并且可能不是研究性别类固醇对AD病变影响的最佳模型。

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