Cellular Polyamines Promote Amyloid-Beta (A尾) Peptide Fibrillation and Modulate the Aggregation Pathways
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- 作者：Jinghui Luo ; Chien-Hung Yu ; Huixin Yu ; Rok Borstnar ; Shina C. L. Kamerlin ; Astrid Gr盲slund ; Jan Pieter Abrahams ; Sebastian K. T. S. W盲rml盲nder
- 刊名：ACS Chemical Neuroscience
- 出版年：2013
- 出版时间：March 20, 2013
- 年：2013
- 卷：4
- 期：3
- 页码：454-462
- 全文大小：490K
- 年卷期：v.4,no.3(March 20, 2013)
- ISSN：1948-7193
文摘
The cellular polyamines spermine, spermidine, and their metabolic precursor putrescine, have long been associated with cell-growth, tumor-related gene regulations, and Alzheimer鈥檚 disease. Here, we show by in vitro spectroscopy and AFM imaging, that these molecules promote aggregation of amyloid-beta (A尾) peptides into fibrils and modulate the aggregation pathways. NMR measurements showed that the three polyamines share a similar binding mode to monomeric A尾(1鈥?0) peptide. Kinetic ThT studies showed that already very low polyamine concentrations promote amyloid formation: addition of 10 渭M spermine (normal intracellular concentration is 1 mM) significantly decreased the lag and transition times of the aggregation process. Spermidine and putrescine additions yielded similar but weaker effects. CD measurements demonstrated that the three polyamines induce different aggregation pathways, involving different forms of induced secondary structure. This is supported by AFM images showing that the three polyamines induce A尾(1鈥?0) aggregates with different morphologies. The results reinforce the notion that designing suitable ligands which modulate the aggregation of A尾 peptides toward minimally toxic pathways may be a possible therapeutic strategy for Alzheimer鈥檚 disease.