State Key Laboratory of Coordination Chemistry, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023, China.
The Brain Cognition and Brain Disease Institute, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong 518055, China.
Aging (Albany NY). 2023 Oct 10;15(19):10580-10592. doi: 10.18632/aging.205095.
Alzheimer's disease (AD) is a chronic neurodegenerative disease and the common cause of dementia. The aggregation of beta-amyloid (Aβ peptide) leading to excessive neuroinflammation is considered to be the neuropathological hallmark of AD, although the precise mechanisms remain unclear. Oligomerization of these peptides may be associated with their 42 amino acid residue arrangement. However, the process of amyloid plaque formation is still not well known. The protein folding-shape code (PFSC) method is a powerful tool to analyze protein confirmation which could exhibit the local structural folding features in detail. In our study, we utilized the PFSC to analyze Aβ peptide in humans and mice and found that mouse Aβ42 is less likely to polymerize than human's. Subsequently, we used the PFSC method to analyze the 42 amino acids of Aβ, transformed some species in human Aβ42 and obtained 7 mutants. We showed that it was not easy to aggregate Aβ in mutants. Herein, inflammatory responses were decreased, as indicated by the expression of cytokines. We confirmed that the neurotoxicity of mutant human Aβ was decreased by preventing peptide aggregation. This may represent a new therapeutic approach for treating AD.
阿尔茨海默病（AD）是一种慢性神经退行性疾病，也是痴呆的常见病因。β-淀粉样蛋白（Aβ 肽）的聚集导致过度神经炎症被认为是 AD 的神经病理学标志，尽管确切的机制仍不清楚。这些肽的寡聚化可能与其 42 个氨基酸残基的排列有关。然而，淀粉样斑块形成的过程仍不清楚。蛋白质折叠形状编码（PFSC）方法是一种强大的分析蛋白质构象的工具，可以详细显示局部结构折叠特征。在我们的研究中，我们利用 PFSC 分析了人类和小鼠的 Aβ 肽，发现小鼠 Aβ42 比人类的 Aβ42 更不容易聚合。随后，我们使用 PFSC 方法分析了 Aβ 的 42 个氨基酸，将人类 Aβ42 中的一些物种转化，并获得了 7 个突变体。我们表明，突变体中 Aβ 不易聚集。在此，细胞因子的表达表明炎症反应降低。我们证实通过防止肽聚合，突变型人 Aβ 的神经毒性降低。这可能代表了治疗 AD 的一种新的治疗方法。
