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Phospholipase A2 inhibitors protect against prion and Abeta mediated synapse degeneration.

Bate C, Tayebi M, Williams A - Mol Neurodegener (2010)

Bottom Line: Pre-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 Abeta1-42.Our results are consistent with the hypothesis that PrP82-146 and Abeta1-42trigger 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pathology and Infectious Diseases, Royal Veterinary College, Hawkshead Lane, North Mymms, Herts, AL9 7TA, UK. cbate@rvc.ac.uk.

ABSTRACT

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 Abeta1-42, 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 A2 inhibitors (AACOCF3, MAFP and aristolochic acids) protected against synapse degeneration in cultured cortical and hippocampal neurones incubated with PrP82-146 or Abeta1-42. Synapse degeneration was also observed following the addition of a specific phospholipase A2 activating peptide (PLAP) and the addition of PrP82-146 or Abeta1-42 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, Abeta1-42 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, Abeta1-42 and PAF induced synapse degeneration.

Conclusions: Our results are consistent with the hypothesis that PrP82-146 and Abeta1-42trigger 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.

No MeSH data available.


Related in: MedlinePlus

Prostaglandin E2 caused synapse degeneration. The synaptophysin content of cortical neurones treated with varying concentrations of prostaglandins E2 (●) D2 (○), F2α(□), I2 (■) or 15d-J2 (▲) for 24 hours. Values shown are the mean average amount of synaptophysin ± SD, n = 9.
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Figure 9: Prostaglandin E2 caused synapse degeneration. The synaptophysin content of cortical neurones treated with varying concentrations of prostaglandins E2 (●) D2 (○), F2α(□), I2 (■) or 15d-J2 (▲) for 24 hours. Values shown are the mean average amount of synaptophysin ± SD, n = 9.

Mentions: Prior studies showed that PAF facilitates the production of prostaglandins [32] suggesting that one or more of the prostaglandins produced in response to PrP82-146, Aβ1-42 or PLAP are responsible for synapse degeneration. This hypothesis was tested by treating cortical neurones with individual prostaglandins. We report that the addition of prostaglandin E2, but not other prostaglandins reduced the amount of synaptophysin in cortical neurones (Figure 9). Prostaglandin E2, acts via specific prostanoid E receptors [33] and pre-treatment with the prostanoid E receptor antagonist AH13205, but not the prostanoid D receptor antagonist BWA868C, prevented the loss of synaptophysin in cortical neurones incubated with PrP82-146, Aβ1-42, PLAP, PAF or prostaglandin E2 (Table 3). Taken together, these results show that the effects of PrP82-146 or Aβ1-42 on synapses were ultimately mediated through prostanoid E receptors.


Phospholipase A2 inhibitors protect against prion and Abeta mediated synapse degeneration.

Bate C, Tayebi M, Williams A - Mol Neurodegener (2010)

Prostaglandin E2 caused synapse degeneration. The synaptophysin content of cortical neurones treated with varying concentrations of prostaglandins E2 (●) D2 (○), F2α(□), I2 (■) or 15d-J2 (▲) for 24 hours. Values shown are the mean average amount of synaptophysin ± SD, n = 9.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2865460&req=5

Figure 9: Prostaglandin E2 caused synapse degeneration. The synaptophysin content of cortical neurones treated with varying concentrations of prostaglandins E2 (●) D2 (○), F2α(□), I2 (■) or 15d-J2 (▲) for 24 hours. Values shown are the mean average amount of synaptophysin ± SD, n = 9.
Mentions: Prior studies showed that PAF facilitates the production of prostaglandins [32] suggesting that one or more of the prostaglandins produced in response to PrP82-146, Aβ1-42 or PLAP are responsible for synapse degeneration. This hypothesis was tested by treating cortical neurones with individual prostaglandins. We report that the addition of prostaglandin E2, but not other prostaglandins reduced the amount of synaptophysin in cortical neurones (Figure 9). Prostaglandin E2, acts via specific prostanoid E receptors [33] and pre-treatment with the prostanoid E receptor antagonist AH13205, but not the prostanoid D receptor antagonist BWA868C, prevented the loss of synaptophysin in cortical neurones incubated with PrP82-146, Aβ1-42, PLAP, PAF or prostaglandin E2 (Table 3). Taken together, these results show that the effects of PrP82-146 or Aβ1-42 on synapses were ultimately mediated through prostanoid E receptors.

Bottom Line: Pre-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 Abeta1-42.Our results are consistent with the hypothesis that PrP82-146 and Abeta1-42trigger 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pathology and Infectious Diseases, Royal Veterinary College, Hawkshead Lane, North Mymms, Herts, AL9 7TA, UK. cbate@rvc.ac.uk.

ABSTRACT

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 Abeta1-42, 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 A2 inhibitors (AACOCF3, MAFP and aristolochic acids) protected against synapse degeneration in cultured cortical and hippocampal neurones incubated with PrP82-146 or Abeta1-42. Synapse degeneration was also observed following the addition of a specific phospholipase A2 activating peptide (PLAP) and the addition of PrP82-146 or Abeta1-42 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, Abeta1-42 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, Abeta1-42 and PAF induced synapse degeneration.

Conclusions: Our results are consistent with the hypothesis that PrP82-146 and Abeta1-42trigger 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.

No MeSH data available.


Related in: MedlinePlus