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

Abstract

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.

Concentration-Dependent Effects of Cholesterol on the Dimerization of Amyloid-β Peptides in Lipid Bilayers

“…38 It is conceivable that Aβ peptides first accumulate into oligomers with more than three peptides, prior to the insertion into the membrane and disruption of the membrane by forming pores or via a detergent-like effect. 5,49 Interestingly, the effect of cholesterol on pore formation of Aβ has been reported by experiments to be non-monotonous, 27 similar to our results. Cholesterol affects the pore formation of Aβ by dual effects that involve direct interaction with Aβ and modulation of the membrane structure.…”

“…48 Mutations of the N-terminal charged residues significantly affect Aβ-mediated membrane leakage. 49 Recent simulations of Aβ42 dimers in the lipid bilayer show that strong interactions between N-terminal regions with the lipid head groups stabilize the dimers at the membrane interface and the membrane environment promotes the formation of β-hairpins in the N-terminal region, which is important for the primary nucleation process. 43 All these studies indicate the critical role of the N-terminal region in directing Aβ self-association and stabilizing the peptide aggregates in the membrane.…”

“…Experiments have demonstrated that N-terminal charged residues play a key role in driving the early adsorption of Aβ to a membrane bilayer and mediating the viscoelastic properties of the membrane-bound Aβ . Mutations of the N-terminal charged residues significantly affect Aβ-mediated membrane leakage . Recent simulations of Aβ42 dimers in the lipid bilayer show that strong interactions between N-terminal regions with the lipid head groups stabilize the dimers at the membrane interface and the membrane environment promotes the formation of β-hairpins in the N-terminal region, which is important for the primary nucleation process .…”