Department of Obstetrics, Gynecology and Women's Health, University of Louisville School of Medicine, Louisville, Kentucky 40292, USA.
J Neuropathol Exp Neurol. 2010 Mar;69(3):253-61. doi: 10.1097/NEN.0b013e3181d072cf.
Amyloid-beta peptide (Abeta) plays an essential pathophysiologic role in Alzheimer disease, and elevation of luteinizing hormone (LH) levels during aging has been implicated in its pathogenesis. To assess the effect of LH receptor deficiency on Abeta accumulation, we generated a bigenic mouse model, APPsw(+)/Lhr(-/-), which 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 Abeta plaques and protein content in the hippocampus and cerebral cortex in both male and female mice. Accordingly, several Abeta deposition-related neuropathologic features and functionally relevant molecules were markedly improved, including decreased astrogliosis, reductions of elevated phosphorylated tau, c-fos, alpha7-nicotinic acetylcholine receptor, and restoration of the altered neuropeptide Y receptors Y1 and Y2. Diminution of Abeta accumulation in the absence of LH receptor supports the contention that dysregulation of LH may impact the pathogenesis of Alzheimer disease. The APPsw(+)/Lhr(-/-) mouse may be a useful tool for advancing understanding of the role of LH-mediated events in Alzheimer disease and a model in which to test therapeutic interventions.
淀粉样蛋白-β肽（Abeta）在阿尔茨海默病的病理生理中起着至关重要的作用，而黄体生成素（LH）水平在衰老过程中的升高与它的发病机制有关。为了评估 LH 受体缺失对 Abeta 积累的影响，我们生成了一种双基因小鼠模型，APPsw(+)/Lhr(-/-)，其在 LH 受体（Lhr）敲除的背景下表达人淀粉样前体蛋白（APPsw）。Lhr 的基因缺失导致雌雄小鼠海马体和大脑皮层中 Abeta 斑块的数量和蛋白含量显著减少。相应地，一些 Abeta 沉积相关的神经病理学特征和功能相关分子得到了显著改善，包括星形胶质细胞增生减少、磷酸化 tau、c-fos、α7-烟碱型乙酰胆碱受体减少，以及改变的神经肽 Y 受体 Y1 和 Y2 的恢复。LH 受体缺失导致 Abeta 积累减少，支持了 LH 失调可能影响阿尔茨海默病发病机制的观点。APPsw(+)/Lhr(-/-)小鼠可能是一种有用的工具，可用于深入了解 LH 介导的事件在阿尔茨海默病中的作用，并可用于测试治疗干预措施。
