Copper complexing decreases the ability of amyloid beta peptide to cross the BBB and enter brain parenchyma.
The amyloid hypothesis states that amyloid beta protein (Abeta) plays a major causal role in the onset of Alzheimer's disease. Toxicity of Abeta can be modified by metal ions. Two mechanisms by which such Abeta and metal ions could interact are by enhanced oxidative stress or by altered fibrillation. Specifically, Abeta fibrillation is increased by aluminum (Al) and copper (Cu) and Al also increases Abeta uptake into brain. Here, we determined whether chelation with Cu would alter uptake of the human or rat 1-42 form of Abeta (Abeta42) by brain or alter Abeta-induced oxidative stress in an immortalized line of rat brain endothelial cells (RBE4). We found that Cu enhanced cytotoxicity of rat, but not of human Abeta, had no effect on glutathione (GSH) or cysteine (CYS) levels. Cu significantly decreased homocysteine (HCYS) levels when complexed with Abeta. Cu chelation did not alter Abeta uptake into brain or other tissues (except for kidney) or alter clearance from blood or brain in vivo, but did increase efflux in an in vitro model of the blood-brain barrier (BBB). Chelation to Cu also impaired the capillary to brain transport of Abeta, an effect opposite to that previously found for chelation of Abeta to Al. These results show that metal ions have varied effects on Abeta uptake by brain and that Cu could be protective against the neurotoxic effects of circulating Abeta.
Mare
Suneetha
S
Department of Chemistry, University of Missouri-Rolla, Rolla, MO 65409, USA.
Penugonda
Suman
S
Robinson
Sandra M
SM
Dohgu
Shinya
S
Banks
William A
WA
Ercal
Nuran
N
D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D002470:Cell Survival; D002614:Chelating Agents / Q000378:metabolism* / Q000494:pharmacology; D003300:Copper / Q000378:metabolism* / Q000494:pharmacology; D042783:Endothelial Cells / Q000378:metabolism; D006801:Humans; D051379:Mice; D008815:Mice, Inbred Strains; D018384:Oxidative Stress; D010446:Peptide Fragments / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D013438:Sulfhydryl Compounds / Q000378:metabolism; D013997:Time Factors
D016229:Amyloid beta-Peptides; D002614:Chelating Agents; D010446:Peptide Fragments; D013438:Sulfhydryl Compounds; C075222:amyloid beta-protein (1-42); D003300:Copper