Progesterone and estrogen regulate Alzheimer-like neuropathology in female 3xTg-AD mice
Progesterone and estrogen regulate Alzheimer-like neuropathology in female 3xTg-AD mice
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DOI：
10.1523/jneurosci.2718-07.2007
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发表时间：
2007-11-28
影响因子：
5.3
通讯作者：
Pike, Christian J.
中科院分区：
文献类型：
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作者：
Carroll, Jenna C.;Rosario, Emily R.;Pike, Christian J.
绝经后女性的雌激素消耗是阿尔茨海默病 (AD) 发展的一个重要危险因素，基于雌激素的激素疗法可能会降低这种风险。然而，黄体酮单独使用以及与雌激素联合使用对 AD 神经病理学的影响仍不清楚。在本研究中，我们使用AD（3xTg-AD）三重转基因小鼠模型来研究雌激素和孕激素对β-淀粉样蛋白（Aβ）积累、tau蛋白过度磷酸化和海马依赖性行为障碍的单独和联合影响。在性腺完整的雌性 3xTg-AD 小鼠中，AD 样神经病理学在 3 个月大时就很明显，并在 12 个月大时逐渐增加，这一时间过程与行为障碍并行。成年雌性 3xTg-AD 小鼠中，卵巢切除引起的性类固醇激素消耗显着增加了 Aβ 的积累，并导致记忆力下降。用雌激素而非黄体酮治疗切除卵巢的 3xTg-AD 小鼠，可以防止这些影响。当雌激素和孕激素联合使用时，孕激素会阻止雌激素 Aβ 积累的有益作用，但不会阻止行为表现。有趣的是，单独使用或与雌激素联合使用时，黄体酮可显着降低 tau 蛋白过度磷酸化。这些结果表明，雌激素和孕激素独立且交互地调节 AD 样神经病理学，并表明优化的激素疗法可能有助于降低绝经后妇女患 AD 的风险。
Estrogen depletion in postmenopausal women is a significant risk factor for the development of Alzheimer's disease (AD), and estrogen-based hormonetherapy may reduce this risk. However, the effects of progesterone both alone and in combination with estrogen on AD neuropathology remain unknown. In this study, we used the triple transgenic mouse model of AD(3xTg-AD) to investigate the individual and combined effects of estrogen and progesterone on beta-amyloid (A beta) accumulation, tau hyperphosphorylation, and hippocampal-dependent behavioral impairments. In gonadally intact female 3xTg-AD mice, AD-like neuropathology was apparent by 3 months of age and progressively increased through age 12 months, a time course that was paralleled by behavioral impairment. Ovariectomy-induced depletion of sex steroid hormones in adult female 3xTg-AD mice significantly increased A beta accumulation and worsened memory performance. Treatment of ovariectomized 3xTg-AD mice with estrogen, but not progesterone, prevented these effects. When estrogen and progesterone were administered in combination, progesterone blocked the beneficial effect of estrogenon A beta accumulation but not on behavioral performance. Interestingly, progesterone significantly reduced tau hyperphosphorylation when administered both alone and in combination with estrogen. These results demonstrate that estrogen and progesterone independently and interactively regulate AD-like neuropathology and suggest that an optimized hormone therapy may be useful in reducing the risk of AD in postmenopausal women.