title: Cellular polyamines promote amyloid-beta (Aβ) peptide fibrillation and modulate the aggregation pathways.
abstract: 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.
authors.affiliation: Gorlaeus Laboratory, Leiden Institute of Chemistry, Leiden University, 2300RA Leiden, The Netherlands.
authors.forename: Jinghui
authors.initials: J
authors.lastname: Luo
authors.forename: Chien-Hung
authors.initials: CH
authors.lastname: Yu
authors.forename: Huixin
authors.initials: H
authors.lastname: Yu
authors.forename: Rok
authors.initials: R
authors.lastname: Borstnar
authors.forename: Shina C L
authors.initials: SC
authors.lastname: Kamerlin
authors.forename: Astrid
authors.initials: A
authors.lastname: Gräslund
authors.forename: Jan Pieter
authors.initials: JP
authors.lastname: Abrahams
authors.forename: Sebastian K T S
authors.initials: SK
authors.lastname: Wärmländer
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D000682:Amyloid / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism*; D011073:Polyamines / Q000737:chemistry / Q000378:metabolism; D011700:Putrescine / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013095:Spermidine / Q000737:chemistry / Q000378:metabolism*; D013096:Spermine / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D011073:Polyamines; C078592:amyloid beta-protein (1-40); D013096:Spermine; D013095:Spermidine; D011700:Putrescine