Phospholipase A2 inhibitors protect against prion and Aβ mediated synapse degeneration

Clive Bate,Alun Williams,Mourad Tayebi

doi:10.1186/1750-1326-5-13

Abstract

BackgroundAn 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 Aβ1-42, a peptide thought to trigger pathogenesis in Alzheimer's disease. A pharmacological approach was used to screen cell signalling pathways involved in synapse degeneration.ResultsPre-treatment with phospholipase A2 inhibitors (AACOCF3, MAFP and aristolochic acids) protected against synapse degeneration in cultured cortical and hippocampal neurones incubated with PrP82-146 or Aβ1-42. Synapse degeneration was also observed following the addition of a specific phospholipase A2 activating peptide (PLAP) and the addition of PrP82-146 or Aβ1-42 activated cytoplasmic phospholipase A2 within synapses. Activation of phospholipase A2 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, Aβ1-42 and PLAP. PAF facilitated the production of prostaglandin E2, which also caused synapse degeneration and pre-treatment with the prostanoid E receptor antagonist AH13205 protected against PrP82-146, Aβ1-42 and PAF induced synapse degeneration.ConclusionsOur results are consistent with the hypothesis that PrP82-146 and Aβ1-42trigger abnormal activation of cytoplasmic phospholipase A2 resident within synapses, resulting in elevated levels of PAF and prostaglandin E2that 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.

Highlights

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
We report that PrP82-146 and Aβ1-42 induced synapse degeneration was prevented by pharmacological inhibition of PLA2 and that both PrP82-146 and Aβ1-42 peptides increased activation of cytoplasmic phospholipase A2 within synapses suggesting that activation of this enzyme triggers synapse degeneration
PLA2 inhibitors protected against PrP82-146 induced synapse degeneration The addition of the prion derived peptide PrP82-146 reduced the synaptophysin content of cortical neurones indicative of a loss of synapses

Summary

Introduction

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. In the transmissible spongiform encephalopathies, otherwise known as the prion diseases, changes in synaptic function and a reduction in synaptophysin levels within the brain occur at a time before any gross neuronal loss is observed [1,2,3]. These synaptic alterations are associated with the accumulation of a differentially folded, and protease-resistant isoform (PrPSc), of the host encoded cellular prion protein (PrPC) [4]. The molecular mechanisms that underlie synapse degeneration in prion diseases are not understood Such processes have been examined by incubating cultured neurones with PrPSc or specific prion-derived peptides. Synthetic peptides containing amino acid residues 82 to 146 (PrP82-146) had similar structural and biochemical properties to PrPSc suggesting that this

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