Amyloid-β Peptide (Aβ) Neurotoxicity Is Modulated by the Rate of Peptide Aggregation: Aβ Dimers and Trimers Correlate with Neurotoxicity

被引:181
作者
Hung, Lin Wai [1 ,2 ,3 ,4 ]
Ciccotosto, Giuseppe D. [1 ,2 ,4 ]
Giannakis, Eleni [3 ]
Tew, Deborah J. [1 ,2 ,4 ]
Perez, Keyla [1 ,2 ,4 ]
Masters, Colin L. [2 ,4 ]
Cappai, Roberto [1 ,2 ,4 ]
Wade, John D. [3 ]
Barnham, Kevin J. [1 ,2 ,4 ]
机构
[1] Univ Melbourne, Dept Pathol, Parkville, Vic 3010, Australia
[2] Univ Melbourne, Mol Sci & Biotechnol Inst Bio21, Parkville, Vic 3010, Australia
[3] Univ Melbourne, Howard Florey Inst Physiol & Med, Parkville, Vic 3010, Australia
[4] Mental Hlth Res Inst, Parkville, Vic 3052, Australia
基金
英国医学研究理事会;
关键词
Alzheimer's disease; amyloid-beta; small soluble oligomers; GxxxG; aggregation; neurotoxicity; lipid;
D O I
10.1523/JNEUROSCI.3916-08.2008
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Alzheimer's disease is an age-related neurodegenerative disorder with its toxicity linked to the generation of amyloid-beta peptide (A beta). Within the A beta sequence, there is a systemic repeat of a GxxxG motif, which theoretical studies have suggested may be involved in both peptide aggregation and membrane perturbation, processes that have been implicated in A beta toxicity. We synthesized modified A beta peptides, substituting glycine for leucine residues within the GxxxG repeat motif (GSL peptides). These GSL peptides undergo beta-sheet and fibril formation at an increased rate compared with wild-type A beta. The accelerated rate of amyloid fibril formation resulted in a decrease in the presence of small soluble oligomers such as dimeric and trimeric forms of A beta in solution, as detected by mass spectrometry. This reduction in the presence of small soluble oligomers resulted in reduced binding to lipid membranes and attenuated toxicity for the GSL peptides. The potential role that dimer and trimer species binding to lipid plays in A beta toxicity was further highlighted when it was observed that annexin V, a protein that inhibits A beta toxicity, specifically inhibited A beta dimers from binding to lipid membranes.
引用
收藏
页码:11950 / 11958
页数:9
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