Prostaglandin D2 mediates neuronal damage by amyloid-β or prions which activates microglial cells

Microglial cells killed neurons damaged following incubation with sub-lethal concentrations of peptides derived from either the human prion protein (HuPrP82-146) or amyloid-beta(1-42) (a peptide found in Alzheimer's disease). HuPrP82-146 or amyloid-beta(1-42) 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-beta(1-42) damaged neurons. The binding of the CD14-IgG chimera to HuPrP82-146 or amyloid-beta(1-42) 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 D-2, or prostaglandin E-2, but not other prostaglandins (F-2 alpha, H-2, 12 or 15-dJ(2)), mimicked the effects of amyloid-beta(1-42) on neurons. Thus, prostaglandin D-2 or E-2 damaged neurons bound the CD14-IgG chimera, and in co-cultures prostaglandin D-2 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 cocultures. These results indicate that prostaglandin D2, produced following activation of COX-1 by sub-lethal concentrations of HuPrP82-146 or amyloid-beta(1-42), causes phenotypic changes in neurons that activates microglial cells and leads to neuronal loss. (c) 2005 Elsevier Ltd. All rights reserved.