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

The body of evidence indicating that oligomers of amyloid β_1-42 (Aβ_1-42) produce toxicity to neurons, together with our demonstration that prostaglandin H₂ (PGH ₂) oligomerizes amyloid β_1-42, led to the examination of the neurotoxicity of amyloid β_1-42 treated with PGH ₂. The neurotoxic effects of Aβ_1-42 incubated with PGH₂ 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 Aβ_1-42 itself, incubated for 24 h, has little or no effect on MTT reduction, Aβ_1-42 24 h after exposure to PGH₂ produced a marked inhibition of MTT reduction, comparable with the q6inhibition resulting from Aβ_1-42 that has been oligomerized by incubation for 6 days. Similar results were obtained when Aβ_1-42 was incubated with levuglandin E₂ (LGE₂), a reactive aldehyde formed by spontaneous rearrangement of PGH₂. The oligomers formed from reaction of Aβ_1-42 with LGE₂ exhibit immunochemical similarity with amyloid-derived diffusible ligands (ADDLs), as determined by analysis of the products of reaction of Aβ_1-42 with LGE₂ using western blotting with an antibody that is selective for ADDLs.