Murakami Kazuma, Suzuki Takashi, Hanaki Mizuho, Monobe Yoko, Akagi Ken-Ichi, Irie Kazuhiro
Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan.
National Institute of Biomedical Innovation, Health and Nutrition, Osaka 567-0085, Japan.
Biochem Biophys Res Commun. 2015 Oct 23;466(3):463-7. doi: 10.1016/j.bbrc.2015.09.051. Epub 2015 Sep 11.
Amyloid fibrils in senile plaque mainly consist of the 40-mer and 42-mer amyloid β-proteins (Aβ40 and Aβ42). Although Aβ42 plays more important role in the pathogenesis of Alzheimer's disease (AD), Aβ40 could be involved in the progression of AD pathology because of its large amount. Recent studies revealed that variable sizes of Aβ oligomers contributed to the neuronal death and cognitive dysfunction. However, how large oligomeric species are responsible for AD pathogenesis remains unclear. We previously proposed a toxic dimer model of Aβ with turn structure at positions 22 and 23 using solid-state NMR and systematic proline replacement. Based on this model, we herein show the synthesis and biological activities of an E22P-Aβ40 dimer at position 30, which was connected to l,l-2,6-diaminopimeric acid. The E22P-Aβ40 dimer formed stable 6∼8-mer oligomers without amyloid fibrils, but was not neurotoxic on human neuroblastoma cells. On the other hand, E22P-Aβ40 generated high molecular-weight oligomers into fibrils, and showed the neurotoxicity. These results suggest that such kind of Aβ40 dimer with a parallel β-sheet might not be pathological.
老年斑中的淀粉样纤维主要由40聚体和42聚体的淀粉样β蛋白（Aβ40和Aβ42）组成。尽管Aβ42在阿尔茨海默病（AD）的发病机制中起更重要的作用，但由于Aβ40数量众多，它也可能参与AD病理过程的进展。最近的研究表明，不同大小的Aβ寡聚体导致神经元死亡和认知功能障碍。然而，大的寡聚体如何导致AD发病机制仍不清楚。我们之前使用固态核磁共振和系统的脯氨酸置换提出了一种Aβ的有毒二聚体模型，该模型在22和23位具有转角结构。基于此模型，我们在此展示了在30位连接l，l-2，6-二氨基庚二酸的E22P-Aβ40二聚体的合成及其生物学活性。E22P-Aβ40二聚体形成稳定的6至8聚体寡聚体而无淀粉样纤维，但对人神经母细胞瘤细胞无神经毒性。另一方面，E22P-Aβ40将高分子量寡聚体转变为纤维，并表现出神经毒性。这些结果表明，这种具有平行β-折叠的Aβ40二聚体可能不是病理性的。
