Protofibrillar intermediates of amyloid β-protein induce acute electrophysiological changes and progressive neurotoxicity in cortical neurons
Protofibrillar intermediates of amyloid β-protein induce acute electrophysiological changes and progressive neurotoxicity in cortical neurons
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DOI：
10.1523/jneurosci.19-20-08876.1999
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发表时间：
1999-10-15
影响因子：
5.3
通讯作者：
Selkoe, DJ
中科院分区：
文献类型：
--
作者：
Hartley, DM;Walsh, DM;Selkoe, DJ
阿尔茨海默氏病（AD）是一种进行性神经退行性疾病，被认为部分由与年龄相关的淀粉样β蛋白（A β）积累引起。在AD脑组织中存在含有丰富的A β衍生的淀粉样纤维的神经炎斑块支持了纤维积累本身是AD中神经元功能障碍的基础的概念。最近的观察已经开始挑战这一假设，表明早期的A β组装体形成的过程中的原纤维也可能在AD发病机制中发挥作用。在这里，我们提出了新的发现，原纤维（PF），淀粉样纤维形成的亚稳态中间体，可以改变神经元的电活动，并导致神经元的损失。低分子量A β（LMW A β）和PF均以时间和浓度依赖性方式在混合脑培养物中可重复诱导毒性。通过刚果红结合或电子显微镜观察，在实验过程中未观察到原纤维形成增加，表明LMW A β和PF的神经毒性不能通过转化为原纤维来解释。重要的是，原纤维，而不是LMW A β，产生了快速增加的EPSP，动作电位，和膜去极化。这些数据表明PF具有与成熟纤维相似的固有生物活性。我们的研究结果提出了AD的临床前和早期临床进展部分由原纤维形成过程中形成的特定A β组装中间体的积累驱动的可能性。
Alzheimer's disease (AD) is a progressive neurodegenerative disorder that is thought to be caused in part by the age-related accumulation of amyloid beta-protein (A beta). The presence of neuritic plaques containing abundant A beta-derived amyloid fibrils in AD brain tissue supports the concept that fibril accumulation per se underlies neuronal dysfunction in AD. Recent observations have begun to challenge this assumption by suggesting that earlier A beta assemblies formed during the process of fibrillogenesis may also play a role in AD pathogenesis. Here, we present the novel finding that protofibrils (PF), metastable intermediates in amyloid fibril formation, can alter the electrical activity of neurons and cause neuronal loss. Both low molecular weight A beta (LMW A beta) and PF reproducibly induced toxicity in mixed brain cultures in a time- and concentration-dependent manner. No increase in fibril formation during the course of the experiments was observed by either Congo red binding or electron microscopy, suggesting that the neurotoxicity of LMW A beta and PF cannot be explained by conversion to fibrils. Importantly, protofibrils, but not LMW A beta, produced a rapid increase in EPSPs, action potentials, and membrane depolarizations. These data suggest that PF have inherent biological activity similar to that of mature fibrils. Our results raise the possibility that the preclinical and early clinical progression of AD is driven in part by the accumulation of specific A beta assembly intermediates formed during the process of fibrillogenesis.