期刊
JOURNAL OF PHYSICAL CHEMISTRY B
卷 125, 期 28, 页码 7671-7678出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jpcb.1c03413
关键词
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资金
- National Institutes of Health [R15GM116006]
- Alzheimer's Association [AARG-17-531423]
The mutations of the N-terminal charged residues of A beta(40) significantly affect the peptide-induced membrane leakage, and the flexible and charge-rich N-terminal region may play a critical role in directing A beta self-association on the membrane surface and stabilizing the peptide aggregates.
Amyloidogenesis of amyloid-beta (A beta) peptides is intimately related to pathological neurodegeneration in Alzheimer's disease. Here, we investigated the membrane damage activity of A beta(40) 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 A beta(40) significantly affect the peptide-induced membrane leakage. The results suggest that favorable electrostatic interactions of the Nterminal charged residues and the phosphatidylcholine membrane surface are crucial in A beta-mediated membrane permeation. The flexible and charge-rich N-terminal region may play a critical role in directing A beta 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 A beta. The results provide new mechanistic insight into the A beta-mediated membrane damage process, which may be critical for understanding the mechanism of A beta neurotoxicity in Alzheimer's disease.
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