Characterization of 8-epiprostaglandin F2alpha as a marker of amyloid beta-peptide-induced oxidative damage.
The amyloid beta-peptide (A beta) is a major component of the neuritic plaques that are a defining histological characteristic of Alzheimer's disease. A beta can be directly toxic and pro-inflammatory to cells in vitro. Numerous reports have shown that oxidative damage and reactive oxygen species play a role in A beta-mediated neurotoxicity. 8-Epiprostaglandin F2alpha (8-isoprostane) is a well characterized product of lipid peroxidation that is formed nonenzymatically in cell membranes following an oxidative insult. We report a time- and concentration-dependent increase in 8-isoprostane levels in rat hippocampal cultures treated with A beta(1-40) or hydrogen peroxide. As evidence that 8-isoprostane production is part of an A beta toxic pathway, alkaline-treated peptide, which shows minimal toxic activity, resulted in greatly attenuated 8-isoprostane production. Although the increase in 8-isoprostane levels preceded cell death, exogenously added 8-isoprostane had no cytotoxic effects. The antioxidants vitamin E and propyl gallate attenuated A beta-induced 8-isoprostane formation yet had no effect on A beta-induced lactate dehydrogenase release. Neither vitamin E nor propyl gallate had any effect on A beta's ability to adopt a beta-pleated sheet structure and deposit on cells as determined by thioflavine S fluorescence. We conclude that 8-isoprostane is an indicator of A beta-induced damage but not necessarily a mediator of A beta-induced neurotoxicity. Also, 8-isoprostane could be a useful marker for assessing oxidative damage in the CNS.
Mark
R J
RJ
Neuroscience Research Division, Eli Lilly and Company, Indianapolis, Indiana, USA.
Fuson
K S
KS
May
P C
PC
D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D052160:Benzothiazoles; D015415:Biomarkers; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D015237:Dinoprost / Q000031:analogs & derivatives* / Q000378:metabolism; D028441:F2-Isoprostanes; D005456:Fluorescent Dyes; D006624:Hippocampus / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000633:toxicity; D007700:Kinetics; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D016877:Oxidants / Q000633:toxicity; D018384:Oxidative Stress / Q000502:physiology*; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D011487:Protein Conformation; D051381:Rats; D013844:Thiazoles
D016229:Amyloid beta-Peptides; D000975:Antioxidants; D052160:Benzothiazoles; D015415:Biomarkers; D028441:F2-Isoprostanes; D005456:Fluorescent Dyes; D016877:Oxidants; D010446:Peptide Fragments; D013844:Thiazoles; C078592:amyloid beta-protein (1-40); C009462:thioflavin T; C075750:8-epi-prostaglandin F2alpha; D015237:Dinoprost; D006861:Hydrogen Peroxide; D007770:L-Lactate Dehydrogenase