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


Address correspondence and reprint requests to Olivier Boutaud, Ph.D., Division of Clinical Pharmacology, Department of Pharmacology, Vanderbilt University, Nashville, TN 37232–6602, USA. E-mail:


The body of evidence indicating that oligomers of amyloid β1−42 (Aβ1−42) produce toxicity to neurons, together with our demonstration that prostaglandin H2 (PGH2) oligomerizes amyloid β1−42, led to the examination of the neurotoxicity of amyloid β1−42 treated with PGH2. The neurotoxic effects of Aβ1−42 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 Aβ1−42 itself, incubated for 24 h, has little or no effect on MTT reduction, Aβ1−42 24 h after exposure to PGH2 produced a marked inhibition of MTT reduction, comparable with the inhibition resulting from Aβ1−42 that has been oligomerized by incubation for 6 days. Similar results were obtained when Aβ1−42 was incubated with levuglandin E2 (LGE2), a reactive aldehyde formed by spontaneous rearrangement of PGH2. The oligomers formed from reaction of Aβ1−42 with LGE2 exhibit immunochemical similarity with amyloid-derived diffusible ligands (ADDLs), as determined by analysis of the products of reaction of Aβ1−42 with LGE2 using western blotting with an antibody that is selective for ADDLs.