Biochem Biophys Res Commun. 2013 Nov 15;441(2):493-8.
Amyloid-β (Aβ) proteins, which consist of 42 amino acids (Aβ1–42), are the major constituent of neuritic plaques that form in the brains of senile patients with Alzheimer’s disease (AD). Several reports state that three aspartic acid (Asp) residues at positions 1, 7, and 23 in Aβ1–42 in the plaques of patients with AD are highly isomerized from the L- to D-form. Using biophysical experiments, the present study shows that simultaneous D-isomerization of Asp residues at positions 7 and 23 (D-Asp(7,23)) enhances oligomerization, fibril formation, and neurotoxic effect of Aβ1–42. In addition, D-isomerization of Asp at position 1 (D-Asp(1)) suppresses malignant effects induced by D-Asp(7,23) of Aβ1–42. These results provide fundamental information to elucidate molecular mechanisms of AD pathogenesis and to develop potent inhibitors of amyloid aggregates and Aβ neurotoxicity.
淀粉样蛋白-β（Aβ）蛋白由 42 个氨基酸组成（Aβ1-42），是老年痴呆症（AD）患者大脑中形成的神经突斑块的主要成分。有几项报告指出，AD 患者斑块中 Aβ1-42 上的 7 位和 23 位的三个天冬氨酸（Asp）残基高度从 L-异构化为 D-形式。本研究通过生物物理实验表明，7 位和 23 位天冬氨酸残基的同时 D-异构化（D-Asp（7,23））增强了 Aβ1-42 的寡聚化、纤维形成和神经毒性作用。此外，1 位天冬氨酸（D-Asp（1））的 D-异构化抑制了 Aβ1-42 的 D-Asp（7,23）诱导的恶性作用。这些结果为阐明 AD 发病机制的分子机制以及开发有效的淀粉样蛋白聚集体和 Aβ 神经毒性抑制剂提供了基础信息。
