PDF(Pubmed)
Abstract：
Amyloid-β (Aβ) is one of the amyloidogenic intrinsically disordered proteins (IDPs) that self-assemble to protein aggregates, incurring cell malfunction and cytotoxicity. While Aβ has been known to regulate multiple physiological functions, such as enhancing synaptic functions, aiding in the recovery of the blood-brain barrier/brain injury, and exhibiting tumor suppression/antimicrobial activities, the hydrophobicity of the primary structure promotes pathological aggregations that are closely associated with the onset of Alzheimer\'s disease (AD). Aβ proteins consist of multiple isoforms with 37-43 amino acid residues that are produced by the cleavage of amyloid-β precursor protein (APP). The hydrolytic products of APP are secreted to the extracellular regions of neuronal cells. Aβ 1-42 (Aβ42) and Aβ 1-40 (Aβ40) are dominant isoforms whose significance in AD pathogenesis has been highlighted in numerous studies to understand the molecular mechanism and develop AD diagnosis and therapeutic strategies. In this review, we focus on the differences between Aβ42 and Aβ40 in the molecular mechanism of amyloid aggregations mediated by the two additional residues (Ile41 and Ala42) of Aβ42. The current comprehension of Aβ42 and Aβ40 in AD progression is outlined, together with the structural features of Aβ42/Aβ40 amyloid fibrils, and the aggregation mechanisms of Aβ42/Aβ40. Furthermore, the impact of the heterogeneous distribution of Aβ isoforms during amyloid aggregations is discussed in the system mimicking the coexistence of Aβ42 and Aβ40 in human cerebrospinal fluid (CSF) and plasma. [BMB Reports 2024; 57(6): 263-272].
摘要：
淀粉样蛋白-β(Aβ)是一种自组装成蛋白质聚集体的淀粉样蛋白(IDPs),引起细胞功能障碍和细胞毒性。虽然已知Aβ调节多种生理功能，比如增强突触功能，帮助恢复血脑屏障/脑损伤，并表现出肿瘤抑制/抗菌活性，一级结构的疏水性促进与阿尔茨海默病（AD）发病密切相关的病理性聚集。Aβ蛋白由具有37-43个氨基酸残基的多个同种型组成,其通过淀粉样蛋白-β前体蛋白(APP)的切割产生。APP的水解产物被分泌到神经元细胞的胞外区。Aβ1-42（Aβ42）和Aβ1-40（Aβ40）是主要的同工型，其在AD发病机理中的意义已在许多研究中得到强调，以了解其分子机制并开发AD诊断和治疗策略。在这次审查中,我们重点研究了Aβ42和Aβ40在由Aβ42的两个额外残基（Ile41和Ala42）介导的淀粉样蛋白聚集的分子机制中的差异。概述了目前对Aβ42和Aβ40在AD进展中的理解，结合Aβ42/Aβ40淀粉样纤维的结构特征，以及Aβ42/Aβ40的聚集机制。此外，在模拟人脑脊液（CSF）和血浆中Aβ42和Aβ40共存的系统中讨论了淀粉样蛋白聚集过程中Aβ同工型异质性分布的影响。
