Effects of the Hydrophilic N‑Terminal Region on Aβ-Mediated Membrane Disruption

Amyloidogenesis of amyloid-β (Aβ) peptides is intimately related to pathological neurodegeneration in Alzheimer’s disease. Here, we investigated the membrane damage activity of Aβ40 and its derivatives that contain mutation at the N-terminal charged residues using a membrane leakage assay. A model 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) phospholipid vesicle encapsulating the fluorescent dye carboxyfluorescein was used in the study. Our results show that the mutations of the N-terminal charged residues of Aβ40 significantly affect the peptide-induced membrane leakage. The results suggest that favorable electrostatic interactions of the N-terminal charged residues and the phosphatidylcholine membrane surface are crucial in Aβ-mediated membrane permeation. The flexible and charge-rich N-terminal region may play a critical role in directing Aβ self-association on the membrane surface and in anchoring and stabilizing the peptide aggregates inserted in the phospholipid membrane, which are closely related with membrane disruption activity of Aβ. The results provide new mechanistic insight into the Aβ-mediated membrane damage process, which may be critical for understanding the mechanism of Aβ neurotoxicity in Alzheimer’s disease.