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Background  An early event in the neuropathology of prion and Alzheimer's diseases is the loss of synapses and a corresponding reduction in the level of synaptophysin, a pre-synaptic membrane protein essential for neurotransmission. The molecular mechanisms involved in synapse degeneration in these diseases are poorly understood. In this study the process of synapse degeneration was investigated by measuring the synaptophysin content of cultured neurones incubated with the prion derived peptide (PrP82-146) or with Aβ 1-42 , a peptide thought to trigger pathogenesis in Alzheimer's disease. A pharmacological approach was used to screen cell signalling pathways involved in synapse degeneration.    Results  Pre-treatment with phospholipase A 2  inhibitors (AACOCF 3 , MAFP and aristolochic acids) protected against synapse degeneration in cultured cortical and hippocampal neurones incubated with PrP82-146 or Aβ 1-42 . Synapse degeneration was also observed following the addition of a specific phospholipase A 2  activating peptide (PLAP) and the addition of PrP82-146 or Aβ 1-42  activated cytoplasmic phospholipase A 2  within synapses. Activation of phospholipase A 2  is the first step in the generation of platelet-activating factor (PAF) and PAF receptor antagonists (ginkgolide B, Hexa-PAF and CV6029) protected against synapse degeneration induced by PrP82-146, Aβ 1-42  and PLAP. PAF facilitated the production of prostaglandin E 2 , which also caused synapse degeneration and pre-treatment with the prostanoid E receptor antagonist AH13205 protected against PrP82-146, Aβ 1-42  and PAF induced synapse degeneration.    Conclusions  Our results are consistent with the hypothesis that PrP82-146 and Aβ 1-42 trigger abnormal activation of cytoplasmic phospholipase A 2  resident within synapses, resulting in elevated levels of PAF and prostaglandin E 2 that cause synapse degeneration. Inhibitors of this pathway that can cross the blood brain barrier may protect against the synapse degeneration seen during Alzheimer's or prion diseases.

Phospholipase A2 inhibitors protect against prion and Aβ mediated synapse degeneration