title: Prostaglandin D2 mediates neuronal damage by amyloid-beta or prions which activates microglial cells.
abstract: Microglial cells killed neurons damaged following incubation with sub-lethal concentrations of peptides derived from either the human prion protein (HuPrP82-146) or amyloid-beta1-42 (a peptide found in Alzheimer's disease). HuPrP82-146 or amyloid-beta1-42 induced phenotypic changes in neurons that caused them to bind a CD14-IgG chimera. In co-cultures microglial cells produced interleukin (IL)-6 in response to HuPrP82-146 or amyloid-beta1-42 damaged neurons. The binding of the CD14-IgG chimera to HuPrP82-146 or amyloid-beta1-42 damaged neurons was reduced by pre-treatment with cyclo-oxygenase (COX)-1 inhibitors and in co-cultures, COX-1 inhibitors significantly increased neuronal survival. Studies with individual prostaglandins demonstrated that the addition of prostaglandin D2, or prostaglandin E2, but not other prostaglandins (F2alpha, H2, I2 or 15-dJ2), mimicked the effects of amyloid-beta1-42 on neurons. Thus, prostaglandin D2 or E2 damaged neurons bound the CD14-IgG chimera, and in co-cultures prostaglandin D2 damaged neurons activated microglial cells. These effects were mediated via the DP prostanoid receptor; DP receptor agonists BW245C or SQ27986 induced neuronal damage, while the DP receptor antagonist BWA868C was neuroprotective in co-cultures. These results indicate that prostaglandin D2, produced following activation of COX-1 by sub-lethal concentrations of HuPrP82-146 or amyloid-beta1-42, causes phenotypic changes in neurons that activates microglial cells and leads to neuronal loss.
authors.affiliation: Department of Pathology and Infectious Diseases, Royal Veterinary College, Hawkshead Lane, North Mymms, Herts, AL9 7TA, UK. cbate@rvc.ac.uk
authors.forename: Clive
authors.initials: C
authors.lastname: Bate
authors.forename: Sarah
authors.initials: S
authors.lastname: Kempster
authors.forename: Alun
authors.initials: A
authors.lastname: Williams
mesh_terms: D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D016718:Arachidonic Acid / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects; D018920:Coculture Techniques; D051545:Cyclooxygenase 1 / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D007074:Immunoglobulin G / Q000276:immunology / Q000502:physiology; D015850:Interleukin-6 / Q000502:physiology; D018950:Lipopolysaccharide Receptors / Q000502:physiology; D008262:Macrophage Activation / Q000187:drug effects; D051379:Mice; D017628:Microglia / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects / Q000473:pathology* / Q000502:physiology*; D009479:Neuropeptides / Q000378:metabolism / Q000494:pharmacology; D018696:Neuroprotective Agents; D010587:Phagocytosis / Q000187:drug effects; D017096:Prion Diseases / Q000473:pathology*; D011328:Prions; D015230:Prostaglandin D2 / Q000502:physiology*
chemical_list: D016229:Amyloid beta-Peptides; D016861:Cyclooxygenase Inhibitors; D007074:Immunoglobulin G; D015850:Interleukin-6; D018950:Lipopolysaccharide Receptors; D009479:Neuropeptides; D018696:Neuroprotective Agents; D011328:Prions; D016718:Arachidonic Acid; D051545:Cyclooxygenase 1; D015230:Prostaglandin D2