Prostaglandin D2 mediates neuronal damage by amyloid-beta 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-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.[1]References
- Prostaglandin D2 mediates neuronal damage by amyloid-beta or prions which activates microglial cells. Bate, C., Kempster, S., Williams, A. Neuropharmacology (2006) [Pubmed]
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