Structural Basis for Increased Toxicity of Pathological Aβ42:Aβ40 Ratios in Alzheimer Disease
Structural Basis for Increased Toxicity of Pathological Aβ42:Aβ40 Ratios in Alzheimer Disease
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DOI：
10.1074/jbc.m111.264473
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发表时间：
2012-02-17
影响因子：
4.8
通讯作者：
Broersen, Kerensa
中科院分区：
文献类型：
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作者：
Pauwels, Kris;Williams, Thomas L.;Broersen, Kerensa
β-淀粉样肽（A β）与阿尔茨海默病（AD）的神经毒性直接相关。在正常生理条件下，该肽的两种最丰富的同种异型物在脑中以类似于1：9的A β（42）：A β（40）比率共存。在家族性AD患者的大脑中，这一比例通常会转移到更高的A β百分比（42），最近已显示这会导致突触毒性增加。这种现象的分子基础尚不清楚。虽然A β（40）和A β（42）单独的聚集特性已经很好地建立，但对混合物的性质知之甚少。我们已经通过几种技术探索了生理相关的A β（42）：A β（40）比率的生物物理和结构特性。我们发现，A beta（40）和A beta（42）直接相互作用，并改变对方的行为。由A β（40）和A β（42）混合物形成的单体和纤维状组装体的结构与单独由这些肽中的任一种形成的结构没有不同。相反，A β（40）和A β（42）的共组装通过改变低聚物形成的模式来影响聚集动力学，如通过溶液核磁共振光谱、高分子量质谱和交叉接种实验的独特组合所证明的。我们将这些观察结果与突触毒性试验和AD患者中观察到的A β（42）：A β（40）相关比率的毒性增强相关。
The beta-amyloid peptide (A beta) is directly related to neurotoxicity in Alzheimer disease (AD). The two most abundant alloforms of the peptide co-exist under normal physiological conditions in the brain in an A beta(42):A beta(40) ratio of similar to 1:9. This ratio is often shifted to a higher percentage of A beta(42) in brains of patients with familial AD and this has recently been shown to lead to increased synaptotoxicity. The molecular basis for this phenomenon is unclear. Although the aggregation characteristics of A beta(40) and A beta(42) individually are well established, little is known about the properties of mixtures. We have explored the biophysical and structural properties of physiologically relevant A beta(42): A beta(40) ratios by several techniques. We show that A beta(40) and A beta(42) directly interact as well as modify the behavior of the other. The structures of monomeric and fibrillar assemblies formed from A beta(40) and A beta(42) mixtures do not differ from those formed from either of these peptides alone. Instead, the co-assembly of A beta(40) and A beta(42) influences the aggregation kinetics by altering the pattern of oligomer formation as evidenced by a unique combination of solution nuclear magnetic resonance spectroscopy, high molecular weight mass spectrometry, and cross-seeding experiments. We relate these observations to the observed enhanced toxicity of relevant ratios of A beta(42):A beta(40) in synaptotoxicity assays and in AD patients.