NR AUMW
AU Bate,C.; Kempster,S.; Williams,A.
TI Prostaglandin D2 mediates neuronal damage by amyloid-beta or prions which activates microglial cells
QU Neuropharmacology 2006 Feb; 50(2): 229-37
PT journal article
AB 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.
MH Amyloid beta-Protein/*toxicity; Animals; Antigens, CD14/physiology; Arachidonic Acid/physiology; Cell Survival/drug effects/physiology; Cerebral Cortex/cytology/drug effects; Coculture Techniques; Cyclooxygenase 1/metabolism; Cyclooxygenase Inhibitors/pharmacology; Immunoglobulin G/immunology/physiology; Interleukin-6/physiology; Macrophage Activation/drug effects; Mice; Microglia/*drug effects; Neurons/drug effects/*pathology/*physiology; Neuropeptides/metabolism/pharmacology; Neuroprotective Agents; Phagocytosis/drug effects; Prion Diseases/*pathology; *Prions; Prostaglandin D2/*physiology; Research Support, Non-U.S. Gov't
AD Department of Pathology and Infectious Diseases, Royal Veterinary College, Hawkshead Lane, North Mymms, Herts, AL9 7TA, UK. cbate@rvc.ac.uk
SP englisch
PO England