Potentiation of beta-amyloid polymerisation by low-density lipoprotein enhances the peptide's vasoactivity.
Alzheimer's disease (AD) is characterised by the accumulation of insoluble beta-amyloid (A beta) fibrils in the brain. Factors that promote A beta fibrillogenesis may influence the pathogenesis of AD and represent targets for therapeutic intervention. Some A beta deposited in AD may originate in the circulation and plasma factors could promote A beta deposition, particularly in the cerebrovasculature. We investigated the effects of plasma low-density lipoprotein (LDL), in both its native and oxidised forms, on A beta(1-40) fibrillogenesis and vasoactivity. LDL enhanced A beta fibrillogenesis in a process dependent on LDL concentration and the oxidative state of the lipoprotein, as indicated by measurements of thiobarbituric acid reactive substances (TBARS) and conjugated dienes. LDL's actions were inhibited by the iA beta 5 peptide, suggesting that LDL-induced A beta polymerisation involved beta-pleated sheet formation. Potentiated A beta polymerisation was reflected by enhanced A beta-mediated vascular responses. Human endothelial cells exposed to fibrillar A beta generated with LDL, especially oxidised LDL, exhibited decreased 20S proteasome activity. Rat aortic ring constriction induced by noradrenaline was enhanced by A beta fibrils generated with LDL, with oxidised LDL producing the more marked effects. Should plasma lipoproteins prove to play a role in cerebral A beta deposition their modification with statins or antioxidants may offer therapeutic benefit.
Stanyer
Lee
L
Department of Medicine, Royal Free and University College Medical School, Sir Jules Thorn Institute, The Middlesex Hospital, Mortimer Street, London W1N 8AA, UK.
Betteridge
D John
DJ
Smith
Christopher C T
CC
D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000494:pharmacology / Q000502:physiology*; D000704:Analysis of Variance; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D008077:Lipoproteins, LDL / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000494:pharmacology*; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism; D009638:Norepinephrine; D010446:Peptide Fragments / Q000494:pharmacology; D011108:Polymers / Q000737:chemistry; D046988:Proteasome Endopeptidase Complex; D014662:Vasoconstrictor Agents
D016229:Amyloid beta-Peptides; D008077:Lipoproteins, LDL; D009097:Multienzyme Complexes; D010446:Peptide Fragments; D011108:Polymers; D014662:Vasoconstrictor Agents; C474023:iAbeta5 peptide; C099252:oxidized low density lipoprotein; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D009638:Norepinephrine