Operational dissection of -amyloid cytopathic effects on cultured neurons
Operational dissection of -amyloid cytopathic effects on cultured neurons
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DOI：
10.1002/jnr.23193
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发表时间：
2013-05-01
影响因子：
4.2
通讯作者：
Poindron, Philippe
中科院分区：
文献类型：
--
作者：
Callizot, Noelle;Combes, Maud;Poindron, Philippe
阿尔茨海默病(AD)主要影响65岁以上的人，患有不同的临床症状，如记忆、思维、语言和学习能力的进行性下降。-淀粉样肽(A)的毒性作用现在已经从不溶的A纤维转变为更小的、可溶的寡聚体A聚集体。对有效的新疗法的迫切需求很高；需要解剖疾病的生理病理方面的强大模型。我们在这里提出了一个模型，可以研究A寡聚体(AO)的四种细胞病变效应：氧化应激、突触丢失、轴突网络解体和细胞死亡。通过产生一种AO溶液，并根据暴露在AO中的浓度和时间，我们已经证明，有可能再现早期效应(氧化应激)和结构变化的长期发展(神经元死亡)。我们的研究表明：1)所有的毒性事件都是按照特定的时间和途径与血管紧张素转换酶联系在一起的；2)血管紧张素转换酶可能是AD发病的关键中间产物。目前的模型使用含有AO的A肽溶液，复制了AD的基本神经病理特征；无论测试哪种神经元(皮质与海马区)，所涉及的效果都是相似的。通过使用一个单一的系统，可以在特定的时间和浓度包含所有的毒性机制，研究每一条涉及的途径，并研究新分子对导致AD发展的不同神经毒性途径的影响。(C)2013年威利期刊公司。
Alzheimer disease (AD) affects mainly people over the age of 65 years, suffering from different clinical symptoms such as progressive decline in memory, thinking, language, and learning capacity. The toxic role of -amyloid peptide (A) has now shifted from insoluble A fibrils to smaller, soluble oligomeric A aggregates. The urgent need for efficient new therapies is high; robust models dissecting the physiopathological aspects of the disease are needed. We present here a model allowing study of four cytopathic effects of A oligomers (AO): oxidative stress, loss of synapses, disorganization of the neurite network, and cellular death. By generating a solution of AO and playing on the concentration of and time of exposure to AO, we have shown that it was possible to reproduce early effects (oxidative stress) and the long-term development of structural alterations (death of neurons). We have shown that 1) all toxic events were linked to AO according to a specific timing and pathway and 2) AO were probably the key intermediates in AD pathogenesis. The present model, using A peptide solution containing AO, reproduced essential neuropathological features of AD; the effects involved were similar whatever the kind of neurons tested (cortical vs. hippocampal). By using a single system, it was possible to embrace all toxic mechanisms at defined times and concentrations, to study each involved pathway, and to study the effects of new molecules on the different neurotoxic pathways responsible for development of AD. (c) 2013 Wiley Periodicals, Inc.