Self‐assembly and Neurotoxicity of Amyloid‐beta (21‐40) Peptide fragment: The regulatory Role of GxxxG Motifs

The three GxxxG repeating motifs from the C‐terminal region of β‐amyloid (Aβ) peptide play a significant role in regulating the aggregation kinetics of the peptide. Mutation of these glycine residues to leucine greatly accelerates the fibrillation process but generates a varied toxicity profile. Using an array of biophysical techniques, we demonstrated the uniqueness of the composite glycine residues in these structural repeats. We used solvent relaxation NMR spectroscopy to investigate the role played by the surrounding water molecules in determining the corresponding aggregation pathway. Notably, the conformational changes induced by Gly33 and Gly37 mutations result in significantly decreased toxicity in a neuronal cell line. Our results indicate that G33xxxG37 is the primary motif responsible for Aβ neurotoxicity, hence providing a direct structure–function correlation. Targeting this motif, therefore, can be a promising strategy to prevent neuronal cell death associated with Alzheimer's and other related diseases, such as type II diabetes and Parkinson's.