Polyamines promote the formation of the A-beta peptide amyloid fibers that are a hallmark of Alzheimer's Disease. Here we show that polyamines interact with non-aggregated A-beta 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 A-beta, even at an A-beta oligomer concentration corresponding to its IC50-concentration. These observations lead us to conclude that polyamines interfere with the more toxic pre-fibrillar conformations and might protect cells by promoting the structural transition of A-beta towards 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 need to be taken into account in understanding the molecular processes related to development of Alzheimer's Disease.