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

• Published in: The journal of physical chemistry. B 2016-08, Vol.120 (30), p.7371-7379
• Main Authors: Nguyen, Hoang Linh, Thi Minh Thu, Tran, Truong, Phan Minh, Lan, Pham Dang, Man, Viet Hoang, Nguyen, Phuong H., Tu, Ly Anh, Chen, Yi-Cheng, Li, Mai Suan
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Amyloid beta-Peptides - chemistry; Amyloid beta-Peptides - metabolism; Humans; Hydrophobic and Hydrophilic Interactions; Kinetics; Molecular Dynamics Simulation; Peptide Fragments - chemistry; Peptide Fragments - metabolism; Protein Aggregates; Protein Structure, Secondary; Thermodynamics
• ISSN: 1520-6106; 1520-5207
• DOI: 10.1021/acs.jpcb.6b06368

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.