Cellular Polyamines Promote Amyloid-Beta (A beta) Peptide Fibrillation and Modulate the Aggregation Pathways

AuthorCount:8;
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 (A beta) peptides into fibrils and modulate the aggregation pathways. NMR measurements showed that the three polyamines share a similar binding mode to monomeric A beta(1-40) peptide. Kinetic ThT studies showed that already very low polyamine concentrations promote amyloid formation: addition of 10 mu M spermine (normal intracellular concentration is similar to 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 beta(1-40) aggregates with different morphologies. The results reinforce the notion that designing suitable ligands which modulate the aggregation of A beta peptides toward minimally toxic pathways may be a possible therapeutic strategy for Alzheimer's disease.

NATURVETENSKAP Biologi Biokemi och molekylärbiologi hsv//swe
NATURAL SCIENCES Biological Sciences Biochemistry and Molecular Biology hsv//eng
Alzheimer's disease
amyloid-beta peptide
natural polyamines
protein-ligand binding
protein aggregation-pathway
peptide fibrillation

Yu, Chien-Hung (författare)
Yu, Huixin (författare)
Borstnar, RokUppsala universitet,Institutionen för cell- och molekylärbiologi (författare)
Kamerlin, LynnUppsala universitet,Beräknings- och systembiologi(Swepub:uu)lynka392 (författare)
Gräslund, AstridStockholms universitet,Institutionen för biokemi och biofysik(Swepub:su)astrid (författare)
Abrahams, Jan Pieter (författare)
Wärmländer, Sebastian K. T. S.Stockholms universitet,Institutionen för biokemi och biofysik(Swepub:su)seb (författare)
Uppsala universitetInstitutionen för cell- och molekylärbiologi (creator_code:org_t)

Ingår i:ACS Chemical Neuroscience: American Chemical Society (ACS)4:3, s. 454-4621948-7193

Av författaren/redakt...: Luo, Jinghui; Yu, Chien-Hung; Yu, Huixin; Borstnar, Rok; Kamerlin, Lynn; Gräslund, Astrid; visa fler...; Abrahams, Jan Pi ...; Wärmländer, Seba ...; visa färre...

Om ämnet

Kungliga biblioteket hanterar dina personuppgifter i enlighet med EU:s dataskyddsförordning (2018), GDPR. Läs mer om hur det funkar här.
Så här hanterar KB dina uppgifter vid användning av denna tjänst.