Division of Molecular Structure, Medical Research Council National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, United Kingdom.
J Biol Chem. 2012 Feb 17;287(8):5650-60. doi: 10.1074/jbc.M111.264473. Epub 2011 Dec 8.
The β-amyloid peptide (Aβ) 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 Aβ(42):Aβ(40) ratio of ∼1:9. This ratio is often shifted to a higher percentage of Aβ(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 Aβ(40) and Aβ(42) individually are well established, little is known about the properties of mixtures. We have explored the biophysical and structural properties of physiologically relevant Aβ(42):Aβ(40) ratios by several techniques. We show that Aβ(40) and Aβ(42) directly interact as well as modify the behavior of the other. The structures of monomeric and fibrillar assemblies formed from Aβ(40) and Aβ(42) mixtures do not differ from those formed from either of these peptides alone. Instead, the co-assembly of Aβ(40) and Aβ(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 Aβ(42):Aβ(40) in synaptotoxicity assays and in AD patients.
β-淀粉样肽（Aβ）与阿尔茨海默病（AD）的神经毒性直接相关。在大脑的正常生理条件下，该肽的两种最丰富的同种型以 Aβ（42）：Aβ（40）的比例约为 1：9 共存。在家族性 AD 患者的大脑中，该比例通常会转移到更高比例的 Aβ（42），最近已证明这会导致突触毒性增加。这种现象的分子基础尚不清楚。尽管 Aβ（40）和 Aβ（42）各自的聚集特性已得到充分证实，但对于混合物的特性却知之甚少。我们已经使用多种技术探索了具有生理相关性的 Aβ（42）：Aβ（40）比例的生物物理和结构特性。我们表明 Aβ（40）和 Aβ（42）直接相互作用，并改变彼此的行为。由 Aβ（40）和 Aβ（42）混合物形成的单体和纤维状组装体的结构与单独使用这些肽形成的结构没有区别。相反，Aβ（40）和 Aβ（42）的共组装通过改变寡聚物形成的模式来影响聚集动力学，这可以通过溶液核磁共振波谱、高分子量质谱和交叉接种实验的独特组合来证明。我们将这些观察结果与在突触毒性测定和 AD 患者中观察到的相关比例的 Aβ（42）：Aβ（40）增强毒性相关联。
