PGH2-derived levuglandin adducts increase the neurotoxicity of amyloid β1-42

The body of evidence indicating that oligomers of amyloid beta(1-42) (A beta(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 A beta(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 A beta(1-42) itself, incubated for 24 h, has little or no effect on MTT reduction, A beta(1-42) 24 h after exposure to PGH(2) produced a marked inhibition of MTT reduction, comparable with the inhibition resulting from A beta(1-42) that has been oligomerized by incubation for 6 days. Similar results were obtained when A beta(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 A beta(1-42) with LGE(2) exhibit immunochemical similarity with amyloid-derived diffusible ligands (ADDLs), as determined by analysis of the products of reaction of A beta(1-42) with LGE(2) using western blotting with an antibody that is selective for ADDLs.