Brain amyloid-β oligomers in ageing and Alzheimer's disease
Brain amyloid-β oligomers in ageing and Alzheimer's disease
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DOI：
10.1093/brain/awt062
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发表时间：
2013-05-01
期刊：
影响因子：
14.5
通讯作者：
Ashe, Karen H.
中科院分区：
文献类型：
--
作者：
Lesne, Sylvain E.;Sherman, Mathew A.;Ashe, Karen H.
阿尔茨海默病在症状发作或神经元死亡前约二十年开始，并且被认为是由致病性淀粉样蛋白-β聚集体引起的，所述淀粉样蛋白-β聚集体引发最终导致广泛神经变性的级联分子事件。微管结合蛋白tau可能介导淀粉样蛋白β在该级联反应中的作用。由不可溶的纤维状β淀粉样蛋白聚集体组成的淀粉样蛋白斑块是阿尔茨海默病最典型的特征。然而，斑块分布与神经退行性变模式之间的对应关系是脆弱的。这种差异刺激了对其他淀粉样蛋白-β聚集体的研究，包括可溶性淀粉样蛋白-β寡聚体。已经在几种小鼠模型中研究了不同的可溶性淀粉样蛋白-β寡聚体，但在人类中没有系统地研究。在这里，我们测量了三个淀粉样蛋白-β寡聚体先前在小鼠模型中描述的淀粉样蛋白-β三聚体，A β *56和淀粉样蛋白-β二聚体-在脑组织中，从75个认知完整的个体，从幼儿到老年人，和58个轻度认知障碍或可能的阿尔茨海默病受损的受试者。在小鼠模型中，淀粉样蛋白β三聚体似乎是A β *56的基本淀粉样蛋白β组装单位，并且在记忆力下降之前存在于年轻小鼠中，人类中的淀粉样蛋白β三聚体存在于儿童和青少年中;它们的水平随着年龄的增长而逐渐上升，并且在70多岁的受试者中显著高于基线。在儿童和年轻人中，A β *56水平可以忽略不计，在40多岁的受试者中显著高于基线，此后稳步上升。β-淀粉样蛋白二聚体在60多岁之前是无法检测到的，然后其水平急剧增加，并与斑块负荷相关。值得注意的是，在认知完整的个体中，我们发现A β *56与两种病理形式的可溶性tau（tau-CP 13和tau-Alz 50）之间存在强正相关性，A β *56与两种突触后蛋白（drepletin和fyn激酶）之间存在负相关性，但淀粉样蛋白β二聚体或淀粉样蛋白β三聚体与tau或突触蛋白之间没有相关性。比较受损与年龄匹配的未受损受试者，我们发现在可能患有阿尔茨海默病的受试者中，淀粉样β二聚体水平最高，但A β *56和淀粉样β三聚体水平最低。总之，在认知正常的成年人中，A β *56在淀粉样蛋白β二聚体或淀粉样蛋白β三聚体之前增加，病理性tau蛋白和突触后蛋白与A β *56相关，但不与淀粉样蛋白β二聚体或淀粉样蛋白β三聚体相关。我们认为A β *56可能在阿尔茨海默病的发病机制中起着非常早期的致病作用。
Alzheimer's disease begins about two decades before the onset of symptoms or neuron death, and is believed to be caused by pathogenic amyloid-beta aggregates that initiate a cascade of molecular events culminating in widespread neurodegeneration. The microtubule binding protein tau may mediate the effects of amyloid-beta in this cascade. Amyloid plaques comprised of insoluble, fibrillar amyloid-beta aggregates are the most characteristic feature of Alzheimer's disease. However, the correspondence between the distribution of plaques and the pattern of neurodegeneration is tenuous. This discrepancy has stimulated the investigation of other amyloid-beta aggregates, including soluble amyloid-beta oligomers. Different soluble amyloid-beta oligomers have been studied in several mouse models, but not systematically in humans. Here, we measured three amyloid-beta oligomers previously described in mouse models-amyloid-beta trimers, A beta*56 and amyloid-beta dimers-in brain tissue from 75 cognitively intact individuals, ranging from young children to the elderly, and 58 impaired subjects with mild cognitive impairment or probable Alzheimer's disease. As in mouse models, where amyloid-beta trimers appear to be the fundamental amyloid-beta assembly unit of A beta*56 and are present in young mice prior to memory decline, amyloid-beta trimers in humans were present in children and adolescents; their levels rose gradually with age and were significantly above baseline in subjects in their 70s. A beta*56 levels were negligible in children and young adults, rose significantly above baseline in subjects in their 40s and increased steadily thereafter. Amyloid-beta dimers were undetectable until subjects were in their 60s; their levels then increased sharply and correlated with plaque load. Remarkably, in cognitively intact individuals we found strong positive correlations between A beta*56 and two pathological forms of soluble tau (tau-CP13 and tau-Alz50), and negative correlations between A beta*56 and two postsynaptic proteins (drebrin and fyn kinase), but none between amyloid-beta dimers or amyloid-beta trimers and tau or synaptic proteins. Comparing impaired with age-matched unimpaired subjects, we found the highest levels of amyloid-beta dimers, but the lowest levels of A beta*56 and amyloid-beta trimers, in subjects with probable Alzheimer's disease. In conclusion, in cognitively normal adults A beta*56 increased ahead of amyloid-beta dimers or amyloid-beta trimers, and pathological tau proteins and postsynaptic proteins correlated with A beta*56, but not amyloid-beta dimers or amyloid-beta trimers. We propose that A beta*56 may play a pathogenic role very early in the pathogenesis of Alzheimer's disease.