Molecular details of aluminium-amyloid β peptide interaction by nuclear magnetic resonance

Alzheimer's disease (AD) is a devastating neurodegenerative condition that poses major challenges to human health. Both amyloid β (Aβ) and metal ions such as aluminium are implicated in the development of AD. By the means of NMR, the interactions of Al³⁺ with Aβ_1-28 peptide as well as the Aβ_1-28 analogues were studied, and the key binding sites of Al³⁺ in Aβ determined. NMR data showed Al³⁺ interacts with Aβ_1-28 at the NH and αH of numerous residues by exhibiting upfield shifts. Using Aβ analogues where His6, His13 and His14 were individually replaced by alanine residue(s), including Aβ H6A, Aβ H13A, Aβ H14A, and Aβ H6,13,14A, the results demonstrated that the histidine residues (His6, His13 and His14) and N-terminal Asp1 were involved in the Al³⁺ coordination. These findings provide, for the first time, the details of the molecular interaction between Al³⁺ and Aβ, which points to the potential role of Al³⁺ in Aβ aggregation, hence in AD development.