Cellular polyamines promote amyloid-Beta (Aβ) peptide fibrillation and modulate the aggregation pathways

Jinghui Luo, Chien Hung Yu, Huixin Yu, Rok Borstnar, Shina C.L. Kamerlin, Astrid Gräslund, Jan Pieter Abrahams, Sebastian K.T.S. Wärmländer

研究成果: Article同行評審

62 引文 斯高帕斯(Scopus)

摘要

The cellular polyamines spermine, spermidine, and their metabolic precursor putrescine, have long been associated with cell-growth, tumor-related gene regulations, and Alzheimer's disease. Here, we show by in vitro spectroscopy and AFM imaging, that these molecules promote aggregation of amyloid-beta (Aβ) peptides into fibrils and modulate the aggregation pathways. NMR measurements showed that the three polyamines share a similar binding mode to monomeric Aβ(1-40) peptide. Kinetic ThT studies showed that already very low polyamine concentrations promote amyloid formation: addition of 10 μM 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 Aβ(1-40) aggregates with different morphologies. The results reinforce the notion that designing suitable ligands which modulate the aggregation of Aβ peptides toward minimally toxic pathways may be a possible therapeutic strategy for Alzheimer's disease.

原文English
頁(從 - 到)454-462
頁數9
期刊ACS Chemical Neuroscience
4
發行號3
DOIs
出版狀態Published - 2013 三月 20

All Science Journal Classification (ASJC) codes

  • 生物化學
  • 生理學
  • 認知神經科學
  • 細胞生物學

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