PGH2-derived levuglandin adducts increase the neurotoxicity of amyloid beta1-42.
The body of evidence indicating that oligomers of amyloid beta(1-42) (Abeta(1-42)) produce toxicity to neurons, together with our demonstration that prostaglandin H(2) (PGH(2)) oligomerizes amyloid beta(1-42), led to the examination of the neurotoxicity of amyloid beta(1-42) treated with PGH(2). The neurotoxic effects of Abeta(1-42) incubated with PGH(2) was examined in primary cultures of cerebral neurons of mice, monitoring the reduction of 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyltetrazolium bromide (MTT) as an indicator of cell toxicity. Whereas Abeta(1-42) itself, incubated for 24 h, has little or no effect on MTT reduction, Abeta(1-42) 24 h after exposure to PGH(2) produced a marked inhibition of MTT reduction, comparable with the inhibition resulting from Abeta(1-42) that has been oligomerized by incubation for 6 days. Similar results were obtained when Abeta(1-42) was incubated with levuglandin E(2) (LGE(2)), a reactive aldehyde formed by spontaneous rearrangement of PGH(2). The oligomers formed from reaction of Abeta(1-42) with LGE(2) exhibit immunochemical similarity with amyloid-derived diffusible ligands (ADDLs), as determined by analysis of the products of reaction of Abeta(1-42) with LGE(2) using western blotting with an antibody that is selective for ADDLs.
Boutaud
Olivier
O
Department of Pharmacology, Vanderbilt University, Nashville 37232-6602, Tennessee, USA. olivier.boutaud@mcmail.vanderbilt.edu
Montine
Thomas J
TJ
Chang
Lei
L
Klein
William L
WL
Oates
John A
JA
D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000196:embryology / Q000473:pathology; D005260:Female; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects* / Q000473:pathology*; D009498:Neurotoxins; D010446:Peptide Fragments / Q000633:toxicity*; D011247:Pregnancy; D044262:Prostaglandin H2 / Q000494:pharmacology*; D011458:Prostaglandins E / Q000494:pharmacology*
D016229:Amyloid beta-Peptides; D009498:Neurotoxins; D010446:Peptide Fragments; D011458:Prostaglandins E; C075222:amyloid beta-protein (1-42); D044262:Prostaglandin H2; C047684:levuglandin E2