Switch Laboratory, Flanders Institute for Biotechnology (VIB), B-3000 Leuven, Belgium.
J Biol Chem. 2012 Oct 26;287(44):36732-43. doi: 10.1074/jbc.M112.394635. Epub 2012 Sep 19.
Current therapeutic approaches under development for Alzheimer disease, including γ-secretase modulating therapy, aim at increasing the production of Aβ(1-38) and Aβ(1-40) at the cost of longer Aβ peptides. Here, we consider the aggregation of Aβ(1-38) and Aβ(1-43) in addition to Aβ(1-40) and Aβ(1-42), in particular their behavior in mixtures representing the complex in vivo Aβ pool. We demonstrate that Aβ(1-38) and Aβ(1-43) aggregate similar to Aβ(1-40) and Aβ(1-42), respectively, but display a variation in the kinetics of assembly and toxicity due to differences in short timescale conformational plasticity. In biologically relevant mixtures of Aβ, Aβ(1-38) and Aβ(1-43) significantly affect the behaviors of Aβ(1-40) and Aβ(1-42). The short timescale conformational flexibility of Aβ(1-38) is suggested to be responsible for enhancing toxicity of Aβ(1-40) while exerting a cyto-protective effect on Aβ(1-42). Our results indicate that the complex in vivo Aβ peptide array and variations thereof is critical in Alzheimer disease, which can influence the selection of current and new therapeutic strategies.
目前正在开发用于阿尔茨海默病的治疗方法，包括γ-分泌酶调节疗法，这些方法旨在增加 Aβ（1-38）和 Aβ（1-40）的产生，代价是更长的 Aβ 肽。在这里，我们考虑除了 Aβ（1-40）和 Aβ（1-42）之外，Aβ（1-38）和 Aβ（1-43）的聚集，特别是它们在代表体内复杂 Aβ 池的混合物中的行为。我们证明 Aβ（1-38）和 Aβ（1-43）分别与 Aβ（1-40）和 Aβ（1-42）聚集相似，但由于短时间尺度构象可塑性的差异，组装和毒性的动力学存在差异。在具有生物学意义的 Aβ混合物中，Aβ（1-38）和 Aβ（1-43）显著影响 Aβ（1-40）和 Aβ（1-42）的行为。Aβ（1-38）的短时间尺度构象灵活性被认为是增强 Aβ（1-40）毒性的原因，同时对 Aβ（1-42）发挥细胞保护作用。我们的结果表明，体内复杂的 Aβ 肽阵列及其变体在阿尔茨海默病中至关重要，这可能会影响当前和新治疗策略的选择。
