Docosahexaenoic acid stabilizes soluble amyloid-beta protofibrils and sustains amyloid-beta-induced neurotoxicity in vitro.
Enrichment of diet and culture media with the polyunsaturated fatty acid docosahexaenoic acid has been found to reduce the amyloid burden in mice and lower amyloid-beta (Abeta) levels in both mice and cultured cells. However, the direct interaction of polyunsaturated fatty acids, such as docosahexaenoic acid, with Abeta, and their effect on Abeta aggregation has not been explored in detail. Therefore, we have investigated the effect of docosahexaenoic acid, arachidonic acid and the saturated fatty acid arachidic acid on monomer oligomerization into protofibrils and protofibril fibrillization into fibrils in vitro, using size exclusion chromatography. The polyunsaturated fatty acids docosahexaenoic acid and arachidonic acid at micellar concentrations stabilized soluble Abeta42 wild-type protofibrils, thereby hindering their conversion to insoluble fibrils. As a consequence, docosahexaenoic acid sustained amyloid-beta-induced toxicity in PC12 cells over time, whereas Abeta without docosahexaenoic acid stabilization resulted in reduced toxicity, as Abeta formed fibrils. Arachidic acid had no effect on Abeta aggregation, and neither of the fatty acids had any protofibril-stabilizing effect on Abeta42 harboring the Arctic mutation (AbetaE22G). Consequently, AbetaArctic-induced toxicity could not be sustained using docosahexaenoic acid. These results provide new insights into the toxicity of different Abeta aggregates and how endogenous lipids can affect Abeta aggregation.
Johansson
Ann-Sofi
AS
Department of Public Health and Caring Sciences, Uppsala University, Rudbeck Laboratory, Sweden. ann-sofi.johansson@pubcare.uu.se
Garlind
Anita
A
Berglind-Dehlin
Fredrik
F
Karlsson
Göran
G
Edwards
Katarina
K
Gellerfors
Pär
P
Ekholm-Pettersson
Frida
F
Palmblad
Jan
J
Lannfelt
Lars
L
D000682:Amyloid / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D016718:Arachidonic Acid / Q000494:pharmacology; D002850:Chromatography, Gel; D020285:Cryoelectron Microscopy; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D004537:Eicosanoic Acids / Q000494:pharmacology; D004591:Electrophoresis, Polyacrylamide Gel; D008823:Micelles; D009154:Mutation; D016716:PC12 Cells; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism / Q000633:toxicity*; D051381:Rats; D013997:Time Factors
D000682:Amyloid; D016229:Amyloid beta-Peptides; D004537:Eicosanoic Acids; D008823:Micelles; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D004281:Docosahexaenoic Acids; D016718:Arachidonic Acid; C094477:arachidic acid