title: Endogenous polyamines reduce the toxicity of soluble aβ peptide aggregates associated with Alzheimer's disease.
abstract: Polyamines promote the formation of the Aβ peptide amyloid fibers that are a hallmark of Alzheimer's disease. Here we show that polyamines interact with nonaggregated Aβ peptides, thereby reducing the peptide's hydrophobic surface. We characterized the associated conformational change through NMR titrations and molecular dynamics simulations. We found that even low concentrations of spermine, sperimidine, and putrescine fully protected SH-SY5Y (a neuronal cell model) against the most toxic conformational species of Aβ, even at an Aβ oligomer concentration that would otherwise kill half of the cells or even more. These observations lead us to conclude that polyamines interfere with the more toxic prefibrillar conformations and might protect cells by promoting the structural transition of Aβ toward its less toxic fibrillar state that we reported previously. Since polyamines are present in brain fluid at the concentrations where we observed all these effects, their activity needs to be taken into account in understanding the molecular processes related to the development of 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: Inayathulla
authors.initials: I
authors.lastname: Mohammed
authors.forename: Sebastian K T S
authors.initials: SK
authors.lastname: Wärmländer
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Hiruma
authors.forename: Astrid
authors.initials: A
authors.lastname: Gräslund
authors.forename: Jan Pieter
authors.initials: JP
authors.lastname: Abrahams
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D006801:Humans; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D011073:Polyamines / Q000737:chemistry / Q000378:metabolism*; D066263:Protein Aggregation, Pathological / Q000378:metabolism* / Q000473:pathology; D017433:Protein Structure, Secondary
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D011073:Polyamines; C078592:amyloid beta-protein (1-40)