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Keywords:

  • amyloid;
  • amyloid-derived diffusible ligands;
  • cyclooxygenase;
  • levuglandin;
  • neurotoxicity;
  • prostaglandin H

Abstract

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.