Interactions of amyloid-β (Aβ) peptides and cellular membranes are proposed to be closely related with Aβ neurotoxicity in Alzheimer’s disease. In this study, we systematically investigated the effect of the N-terminal hydrophilic region of Aβ40 on its amyloidogenesis and interaction with supported phospholipid bilayer. Our results show that modulation of the charge properties of the dynamic N-terminal region dramatically influences the aggregation properties of Aβ. Furthermore, our results demonstrate that the N-terminal charged residues play a crucial role in driving the early adsorption and latter remobilization of the peptide on membrane bilayer, and mediating the rigidity and viscoelasticity properties of the bound Aβ40 at the membrane interface. The results provide new mechanistic insight into the early Aβ-membrane interactions and binding, which may be critical for elucidating membrane-mediated Aβ amyloidogenesis in a physiological environment and unravelling the origin of Aβ neurotoxicity.

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