Down-regulation of serum gonadotropins is as effective as estrogen replacement at improving menopause-associated cognitive deficits.
Down-regulation of serum gonadotropins is as effective as estrogen replacement at improving menopause-associated cognitive deficits.
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DOI：
10.1111/j.1471-4159.2009.06502.x
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发表时间：
2010-02
影响因子：
4.7
通讯作者：
Casadesus G
中科院分区：
文献类型：
--
作者：
Bryan KJ;Mudd JC;Richardson SL;Chang J;Lee HG;Zhu X;Smith MA;Casadesus G
虽然雌激素（E2）被认为在与年龄相关的认知衰退、神经元可塑性以及阿尔茨海默病（AD）的发病机制中起重要作用，但雌激素发挥其有益作用的机制存在争议。在这方面，女性雌激素水平下降会因反馈抑制的丧失导致促性腺激素如黄体生成素（LH）增加。与雌激素一样，LH受激素替代疗法（HRT）调节，而且AD患者的血清LH水平高于年龄匹配的对照组。在此，我们证明使用促性腺激素释放激素超强类似物醋酸亮丙瑞林下调卵巢切除术后升高的LH，在没有E2的情况下可改善莫里斯水迷宫和Y型迷宫测试中的认知功能。此外，我们的数据表明这些作用与雌激素受体α和β的调节无关，也与CYP19和StAR的激活无关，这表明内源性E2的产生没有增加。然而，与认知改善相关的通路如CaMKII和GluR1ser831被亮丙瑞林治疗上调，但不被长期慢性E2替代上调。我们的研究结果表明，促性腺激素的下调在调节认知方面与E2同样有效，但可能通过不同的分子机制起作用。这些发现为治疗更年期/年龄相关的认知衰退和/或预防AD的发展提供了一种潜在的新型保护策略。
While estrogen (E2) is thought to play an important role in age-related cognitive decline, neuronal plasticity, as well as the pathogenesis of Alzheimer disease (AD), the mechanisms by which estrogen exerts its beneficial effects are controversial. In this regard, declining levels of estrogen in women result in increases in gonadotropins such as luteinizing hormone (LH) through loss of feedback inhibition. LH, like estrogen, is modulated by hormone replacement therapy (HRT) and serum levels of LH are higher in AD patients compared to aged-matched controls. Here, we demonstrate that the downregulation of elevations in LH that follow ovariectomy using the gonadotropin releasing hormone super-analogue, leuprolide acetate, improves cognitive function in the Morris water maze and Y-maze tests in the absence of E2. Furthermore, our data suggest that these effects are independent of the modulation of estrogen receptors α and β, or activation of CYP19 and StAR which suggests increased production of endogenous E2. However, pathways associated with improved cognition such as CaMKII and GluR1ser831 are upregulated by leuprolide treatment but not by chronic long-term E2 replacement. Our findings suggest that downregulation of gonadotropins is as effective as E2 in modulating cognition but likely acts through different molecular mechanisms. These findings provide a potential novel protective strategy to treat menopause/age-related cognitive decline and/or prevent the development of AD.
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影响因子：
4.8
作者：
Apaja, PM;Harju, KT;Rajaniemi, HJ
通讯作者：
Rajaniemi, HJ
影响因子：
2.2
作者：
Dumas, TC
通讯作者：
Dumas, TC
影响因子：
4.4
作者：
Cimarosti, H;Siqueira, IR;Salbego, C
通讯作者：
Salbego, C
影响因子：
--
作者：
den Heijer, T;Geerlings, MI;Breteler, MMB
通讯作者：
Breteler, MMB
影响因子：
6.1
作者：
COUZINET, B;SCHAISON, G
通讯作者：
SCHAISON, G