Melanocortins protect against progression of Alzheimer's disease in triple-transgenic mice by targeting multiple pathophysiological pathways
Melanocortins protect against progression of Alzheimer's disease in triple-transgenic mice by targeting multiple pathophysiological pathways
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DOI：
10.1016/j.neurobiolaging.2013.08.030
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发表时间：
2014-03-01
影响因子：
4.2
通讯作者：
Guarini, Salvatore
中科院分区：
文献类型：
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作者：
Giuliani, Daniela;Bitto, Alessandra;Guarini, Salvatore
除了特定的触发原因，阿尔茨海默病（AD）涉及急性和慢性神经退行性疾病共同的病理生理途径。黑素皮质素在实验性急性神经退行性疾病中诱导神经保护，在ad型痴呆患者的偶尔研究中发现低黑素皮质素水平。在这里，我们研究了黑素皮质素在慢性神经退行性疾病AD中可能的神经保护作用，通过12周大的（研究开始时）三转基因（3xTg-AD）小鼠携带人类转基因APP(Swe), PS1（M146V）和tau（P301L）。每天1次，直至研究结束（30周龄），用黑素皮质素类似物[Nle(4),D-Phe(7)]- α -促黑素细胞激素（ndp - α - msh）治疗3xTg-AD小鼠，降低大脑皮层/海马磷酸化/所有ad相关生物标志物（淀粉样蛋白/tau级联，氧化/亚氧化应激，炎症，凋亡的介质）的水平，减少神经元损失，诱导突触活性依赖基因Zif268的过度表达，与盐水处理的3xTg-AD小鼠相比，认知功能有所改善。黑素皮质素MC4受体的药物阻断阻断了ndp - α - msh的所有神经保护作用。我们的研究首次确定了一类药物，MC4受体刺激黑素皮素，能够通过靶向β -淀粉样蛋白和tau蛋白上下游的病理生理机制来对抗实验性AD的进展。这些数据可能具有重要的临床意义。(C) 2014爱思唯尔公司版权所有。
Besides specific triggering causes, Alzheimer's disease (AD) involves pathophysiological pathways that are common to acute and chronic neurodegenerative disorders. Melanocortins induce neuroprotection in experimental acute neurodegenerative conditions, and low melanocortin levels have been found in occasional studies performed in AD-type dementia patients. Here we investigated the possible neuroprotective role of melanocortins in a chronic neurodegenerative disorder, AD, by using 12-week-old (at the start of the study) triple-transgenic (3xTg-AD) mice harboring human transgenes APP(Swe), PS1(M146V), and tau(P301L). Treatment of 3xTg-AD mice, once daily until the end of the study (30 weeks of age), with the melanocortin analog [Nle(4),D-Phe(7)]-alpha-melanocyte-stimulating hormone (NDP-alpha-MSH) reduced cerebral cortex/hippocampus phosphorylation/level of all AD-related biomarkers investigated (mediators of amyloid/tau cascade, oxidative/nitrosative stress, inflammation, apoptosis), decreased neuronal loss, induced over-expression of the synaptic activity-dependent gene Zif268, and improved cognitive functions, relative to saline-treated 3xTg-AD mice. Pharmacological blockade of melanocortin MC4 receptors prevented all neuroprotective effects of NDP-alpha-MSH. Our study identifies, for the first time, a class of drugs, MC4 receptor-stimulating melanocortins, that are able to counteract the progression of experimental AD by targeting pathophysiological mechanisms up- and down-stream of beta-amyloid and tau. These data could have important clinical implications. (C) 2014 Elsevier Inc. All rights reserved.