Down-regulation of serum gonadotropins but not estrogen replacement improves cognition in aged-ovariectomized 3xTg AD female mice.
Down-regulation of serum gonadotropins but not estrogen replacement improves cognition in aged-ovariectomized 3xTg AD female mice.
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DOI：
10.1111/jnc.12706
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发表时间：
2014-07
影响因子：
4.7
通讯作者：
Casadesus G
中科院分区：
文献类型：
--
作者：
Palm R;Chang J;Blair J;Garcia-Mesa Y;Lee HG;Castellani RJ;Smith MA;Zhu X;Casadesus G
阿尔茨海默病（AD）的发展与雌激素和促性腺激素（如黄体生成素（LH））的失调有关。在这项研究中，我们发现卵巢切除术后老年雌性3xTg - AD小鼠海马中的AD病理变化增加，且雌激素治疗或血清LH水平的下调都无法使其降低。尽管这些治疗对AD病理没有影响，但血清LH（而非雌激素）的下调改善了与神经元可塑性相关的因素，如空间记忆、糖原合成酶激酶 - 3β的抑制、β - 连环蛋白的表达以及脑源性神经营养因子的转录。与之前在较年轻小鼠中的研究不同，雌激素替代不能挽救行为缺陷、减少糖原合成酶激酶 - 3β的抑制以及增加海马中tau蛋白的磷酸化。至关重要的是，在与空间记忆相关的区域，血清LH与脑LH呈负相关，且脑LH的增加与认知改善相关。这与人类女性AD大脑中的变化相似，与年龄和死后间隔（PMI）匹配的健康对照组相比，人类女性AD大脑中脑LH的mRNA显著减少。综上所述，这些发现应促进对与AD认知缺陷相关的LH依赖机制以及雌激素在老年大脑中的作用的进一步研究。
Development of Alzheimer’s disease (AD) has been linked to the de-regulation of estrogen and gonadotropins such as luteinizing hormone (LH). In this study, we found increases in AD pathology in the hippocampi of aged female 3xTg AD mice after ovariectomy that were unable to be reduced by estrogen therapy or down-regulation of serum LH levels. Despite the lack of effect of these treatments on AD pathology, down-regulation of serum LH but not estrogen improved factors associated with neuronal plasticity such as spatial memory, inhibition of glycogen synthase kinase-3 beta, expression of beta-catenin, and brain-derived neurotrophic factor transcription. Contrasting previous studies in younger mice, estrogen replacement was not able to rescue behavioral deficits, reduced glycogen synthase kinase-3 beta inhibition and increased hippocampal phosphorylation of tau. Of critical importance, serum LH was negatively correlated with brain LH in regions associated with spatial memory, and increases in brain LH correlated with cognitive improvement. This paralleled changes in human female AD brains which showed a significant reduction in brain LH mRNA compared to healthy age- and PMI-matched controls. Taken together, these findings should promote further research into the LH-dependent mechanisms associated with AD cognitive deficits as well as the effects of estrogen within the aged brain.