BACKGROUND: The importance of aromaticity vs. hydrophobicity of the central hydrophobic core (CHC, residues 17-20) in governing fibril formation in Aβ(1-42) has been the focus of an ongoing debate in the literature.
BACKGROUND: Mutations in the CHC (especially at Phe19 and Phe20) have been used to examine the relative impact of hydrophobicity and aromaticity on the degree of aggregation of Aβ(1-42). However, the results have not been conclusive.
METHODS: Partial least squares (PLS) modeling of aggregation rates, using reduced properties of a series of position 19 mutants, was employed to identify the physicochemical properties that had the greatest impact on the extent of aggregation.
RESULTS: The PLS models indicate that hydrophobicity at position 19 of Aβ(1-42) appears to be the primary and dominant factor in controlling Aβ(1-42) aggregation, with aromaticity having little effect.
CONCLUSIONS: This study illustrates the value of using reduced properties of amino acids in conjunction with PLS modeling to investigate mutational effects in peptides and proteins, as the reduced properties can capture in a quantitative manner the different physicochemical properties of the amino acid side chains. In this particular study, hydrophobicity at position 19 was determined to be the dominant property controlling aggregation, while size, charge, and aromaticity had little impact.

Alzheimer\'s disease (AD) is characterized by the amyloid-beta peptide (Aβ) misfolding to form aberrant amyloid aggregates in the brain. Although recent evidence implicates that amyloid deposition in vivo is highly related to biomembranes, how the characteristic lipid components of neuronal membranes mediate this process remains to be fully elucidated. Herein, we established vesicle models to mimic exosomes and investigated their influence on the kinetics of Aβ(1-42) amyloidosis. By using ternary vesicles composed of three brain lipids monosialoganglioside GM1, cholesterol and sphingomyelin, we found that GM1 could regulate peptide fibrillation by facilitating the conformational transition of Aβ(1-42), and further quantitatively analyzed the influence of GM1-containing vesicles on the kinetics of Aβ(1-42) fibrillation. In addition, GM1-containing vesicles induced the formation of Aβ(1-42) fibrils at low concentrations, and these fibrils were toxic to PC12 cells. By analyzing the role of GM1 in this ternary mixture of membranes at the molecular level, we confirmed that GM1 clusters are presented as attachment sites for peptides, thus promoting the fibrillation of Aβ(1-42).