Aβ41 Aggregates More Like Aβ40 than Like Aβ42: In Silico and in Vitro Study

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• 作者：Hoang Linh Nguyen ; Tran Thi Minh Thu ; Phan Minh Truong ; Pham Dang Lan ; Viet Hoang Man ; Phuong H. Nguyen ; Ly Anh Tu ; Yi-Cheng Chen ; Mai Suan Li
• 刊名：Journal of Physical Chemistry B
• 出版年：2016
• 出版时间：August 4, 2016
• 年：2016
• 卷：120
• 期：30
• 页码：7371-7379
• 全文大小：547K
• 年卷期：0
• ISSN：1520-5207

文摘

Formation of intracellular plaques and small oligomeric species of amyloid β (Aβ) peptides inside neurons is a hallmark of Alzheimer’s disease. The most abundant Aβ species in the brain are Aβ1-40 and Aβ1-42, which are composed, respectively, of 40 and 42 residues. Aβ1-42 differs from Aβ1-40 only in two residues, Ile41 and Ala42, yet it shows remarkably faster aggregation and greater neurotoxicity than Aβ1-40. Thus, it is crucial to understand the relative contributions of Ile41 and Ala42 to these distinct behaviors. To achieve this, secondary structures of the Aβ1-41 monomer, which contribute to aggregation propensity, were studied by all-atom molecular dynamics simulation in an implicit solvent and compared to those of Aβ1-40 and Aβ1-42. We find that the secondary structure populations of Aβ1-41 are much closer to those of Aβ1-40 than to those of Aβ1-42, suggesting that Aβ1-41 and Aβ1-40 are likely to have similar aggregation properties. This prediction was confirmed through a thioflavin-T aggregation assay. Thus, our finding indicates that the hydrophobic residue at position 42 is the major contributor to the increased fibril formation rates and consequently neurotoxicity of Aβ peptides.