Testosterone regulation of Alzheimer-like neuropathology in male 3xTg-AD mice involves both estrogen and androgen pathways.
Testosterone regulation of Alzheimer-like neuropathology in male 3xTg-AD mice involves both estrogen and androgen pathways.
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DOI：
10.1016/j.brainres.2010.08.068
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发表时间：
2010-11-04
期刊：
影响因子：
2.9
通讯作者：
Pike CJ
中科院分区：
文献类型：
--
作者：
Rosario ER;Carroll J;Pike CJ
正常的、与年龄相关的雄激素睾酮耗竭是男性阿尔茨海默病（AD）的危险因素。以前，我们报道，实验雄激素耗竭显着加速AD样神经病理学的发展，在3xTg-AD三转基因小鼠模型的AD，雄激素治疗的效果防止。由于睾酮在脑中代谢为雄激素双氢睾酮（DHT）和雌激素17β-雌二醇（E2），因此睾酮可通过雄激素和/或雌激素途径介导其作用。为了确定雄激素和雌激素途径在调节AD样神经病理学中的作用，我们比较了睾酮（T）及其代谢产物DHT和E2在通过性腺切除术（GDX）耗尽内源性类固醇激素的雄性3xTg-AD小鼠中的作用。雄性3xTg-AD小鼠为假GDX或GDX，立即用载体、T、DHT或E2处理，4个月后评价AD样神经病理学的两个指标，β-淀粉样蛋白（Aβ）积累和tau过度磷酸化。与假GDX小鼠相比，我们观察到GDX小鼠下托、海马和杏仁核中Aβ蓄积显著增加。用T处理GDX小鼠可防止所有三个脑区中Aβ积聚的增加。DHT治疗产生了类似的结果，显著减少了Aβ在大脑区域的蓄积。有趣的是，E2阻止了海马中Aβ的积聚，但仅对下托和杏仁核产生部分影响。在假GDX雄性3xTg-AD小鼠中tau过度磷酸化的水平是适度的，并且GDX仅略微增加。用T或E2而不是DHT治疗GDX小鼠将tau过度磷酸化降低至低于在假手术动物中观察到的水平。这些数据表明，睾酮通过雄激素和雌激素途径调节Aβ病理，并主要通过雌激素途径减少tau病理。这些发现进一步定义了参与调节AD相关病理的激素途径，这些信息对于理解疾病病因和开发特定途径的激素干预措施非常重要。
Normal, age-related depletion of the androgen testosterone is a risk factor for Alzheimer’s disease (AD) in men. Previously, we reported that experimental androgen depletion significantly accelerates development of AD-like neuropathology in the 3xTg-AD triple-transgenic mouse model of AD, an effect prevented by androgen treatment. Because testosterone is metabolized in brain into both the androgen dihydrotestosterone (DHT) and the estrogen 17β-estradiol (E2), testosterone can mediate its effects through androgen and or estrogen pathways. To define the role of androgen and estrogen pathways in regulation of AD-like neuropathology, we compared the effects of testosterone (T) and its metabolites DHT and E2 in male 3xTg-AD mice depleted of endogenous sex steroid hormones by gonadectomy (GDX). Male 3xTg-AD mice were sham GDX or GDX, immediately treated with vehicle, T, DHT, or E2, and 4 months later evaluated for two indices of AD-like neuropathology, β-amyloid (Aβ) accumulation and tau hyperphosphorylation. In comparison to sham GDX mice, we observed a significant increase in Aβ accumulation in GDX mice in subiculum, hippocampus, and amygdala. Treatment of GDX mice with T prevented the increased Aβ accumulation in all three brain regions. DHT treatment yielded similar results, significantly reducing Aβ accumulation across brain regions. Interestingly, E2 prevented Aβ accumulation in hippocampus but exerted only partial effects in subiculum and amygdala. Levels of tau hyperphosphorylation in sham GDX male 3xTg-AD mice were modest and only slightly increased by GDX. Treatment of GDX mice with T or E2 but not DHT reduced tau hyperphosphorylation to levels lower than observed in sham animals. These data suggest that testosterone regulates Aβ pathology through androgen and estrogen pathways and reduces tau pathology largely through estrogen pathways. These findings further define hormone pathways involved in regulation of AD-related pathology, information that is important for understanding disease etiology and developing pathway-specific hormone interventions.
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影响因子：
3.2
作者：
Handa RJ;Weiser MJ;Zuloaga DG
通讯作者：
Zuloaga DG
影响因子：
5.8
作者：
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通讯作者：
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DOI：
10.1073/pnas.97.3.1202
发表时间：
2000-02-01
影响因子：
11.1
作者：
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通讯作者：
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作者：
Carroll, Jenna C.;Rosario, Emily R.;Pike, Christian J.
通讯作者：
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影响因子：
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作者：
Carroll, Jenna C.;Pike, Christian J.
通讯作者：
Pike, Christian J.