Genetic ablation of luteinizing hormone receptor improves the amyloid pathology in a mouse model of Alzheimer disease.
Genetic ablation of luteinizing hormone receptor improves the amyloid pathology in a mouse model of Alzheimer disease.
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DOI：
10.1097/nen.0b013e3181d072cf
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发表时间：
2010-03
影响因子：
3.2
通讯作者：
Lei Z
中科院分区：
文献类型：
--
作者：
Lin J;Li X;Yuan F;Lin L;Cook CL;Rao ChV;Lei Z
淀粉样蛋白-β肽(A-β)在阿尔茨海默病(AD)中起着重要的病理生理作用，衰老过程中黄体生成素(LH)水平的升高可能与AD的发病有关。为了评估黄体生成素受体缺陷对Aβ蓄积的影响，我们建立了双基因小鼠模型APPsw+/LHR−/−，该模型在黄体生成素受体基因敲除的背景下表达人淀粉样前体蛋白(APPsw)。LHR的基因消融导致雄性和雌性小鼠海马区和大脑皮层Aβ斑块数量和蛋白质含量显著减少。相应地，一些与Aβ沉积相关的神经病理特征和功能相关分子明显改善，包括星形胶质细胞减少，升高的磷酸化tau，c-fos，α7-烟碱型乙酰胆碱受体减少，以及神经肽Y受体Y1和Y2的恢复。在缺乏促黄体生成素的情况下，A-β积聚的减少支持了黄体生成素失调可能影响AD发病机制的观点。APPsw+/LHR−/−小鼠可能是一个有用的工具，可以促进对黄体生成素介导的事件在AD中的作用的理解，并成为测试治疗干预措施的模型。
Amyloid-β peptide (Aβ) plays an essential pathophysiological role in Alzheimer disease (AD) and elevation of luteinizing hormone (LH) levels during aging has been implicated in its pathogenesis. To assess the effect of LH receptor deficiency on Aβ accumulation, we generated a bigenic mouse model APPsw+/Lhr−/− that expresses human amyloid precursor protein (APPsw) in the background of LH receptor (Lhr) knockout. Genetic ablation of Lhr resulted in a significant decrease in the number of Aβ plaques and protein content in the hippocampus and cerebral cortex in both male and female mice. Accordingly, several Aβ deposition-related neuropathologic features and functionally relevant molecules were markedly improved, including decreased astrogliosis, reductions of elevated phosphorylated tau, c-fos, α7-nicotinic acetylcholine receptor, and restoration of the altered neuropeptide Y receptors Y1 and Y2. Diminution of Aβ accumulation in the absence of LHR supports the contention that dysregulation of LH may impact the pathogenesis of AD. The APPsw+/Lhr−/− mouse may be a useful tool for advancing understanding of the role of LH-mediated events in AD and a model in which to test therapeutic interventions.