Laboratory of Molecular Neurogenetics, Department of Psychiatry, Institute of Psychiatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
J Neurochem. 2010 Feb;112(4):843-53. doi: 10.1111/j.1471-4159.2009.06490.x. Epub 2009 Nov 11.
Alzheimer's disease (AD) is characterized by deposition of amyloid-beta peptide plaque, disrupted amyloid-beta-precursor protein (APP) metabolism, hyperphosphorylation of Tau leading to neurofibrillary tangles and associated neurotoxicity. Moreover, there is synaptic loss in AD, which occurs early and may precede frank amyloidosis. The central cholinergic system is especially vulnerable to the toxic events associated with AD, and reduced acetylcholine levels in specific brain regions is thought to be central to memory deficits in AD. First-generation cholinesterase inhibitors have provided only symptomatic relief to patients with AD by prolonging the action of remaining acetylcholine with little or no change in the course of the disease. Some second-generation cholinesterase inhibitors are multifunctional drugs that may provide more than purely palliative results. To evaluate the effects of the dual acetylcholinesterase and butyrylcholinesterase inhibitor rivastigmine on key aspects of AD, embryonic day 16 rat primary cortical cultures were treated with rivastigmine under media conditions observed to induce time-dependent neurodegeneration. Samples were subjected to western blotting and immunocytochemistry techniques to determine what influence this drug may have on synaptic proteins and neuronal morphology. There was a strong increase in relative cell viability associated with rivastigmine treatment. Significant dose-dependent increases were observed in the levels of synaptic markers synaptosomal-associated protein of 25 kDa (SNAP-25) and synaptophysin, as well as the neuron-specific form of enolase. Together with an observed enhancement of neuronal morphology, our results suggest a rivastigmine-mediated novel neuroprotective and/or neurorestorative effects involving the synapse. Our observations may explain the potential for rivastigmine to alter the course of AD, and warrant further investigations into using butyrylcholinesterase inhibition as a therapeutic strategy for AD, especially with regard to restoration of synaptic function.
阿尔茨海默病（AD）的特征是淀粉样β肽斑块的沉积、淀粉样前体蛋白（APP）代谢紊乱、Tau 的过度磷酸化导致神经原纤维缠结和相关的神经毒性。此外，AD 还存在突触丧失，这种丧失发生较早，可能早于明显的淀粉样变性。中枢胆碱能系统特别容易受到与 AD 相关的毒性事件的影响，特定脑区乙酰胆碱水平的降低被认为是 AD 患者记忆缺陷的核心。第一代胆碱酯酶抑制剂通过延长剩余乙酰胆碱的作用，为 AD 患者提供了仅对症的缓解，对疾病的进程几乎没有或没有任何改变。一些第二代胆碱酯酶抑制剂是多功能药物，可能提供的不仅仅是姑息性结果。为了评估双重乙酰胆碱酯酶和丁酰胆碱酯酶抑制剂利凡斯的明对 AD 关键方面的影响，在诱导时间依赖性神经退行性变的培养基条件下，用利凡斯的明处理胚胎 16 天大鼠原代皮质培养物。将样品进行 Western 印迹和免疫细胞化学技术，以确定这种药物对突触蛋白和神经元形态可能有什么影响。与利凡斯的明治疗相关的细胞存活率有很强的增加。观察到突触标志物突触相关蛋白 25kDa（SNAP-25）和突触小体素以及神经元特异性烯醇化酶的水平呈剂量依赖性显著增加。与观察到的神经元形态增强一起，我们的结果表明利凡斯的明介导的新型神经保护和/或神经修复作用涉及突触。我们的观察结果可能解释了利凡斯的明改变 AD 进程的潜力，并证明进一步研究丁酰胆碱酯酶抑制作为 AD 的治疗策略是合理的，特别是在恢复突触功能方面。
