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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

PAF receptor antagonists protected against PrP82-146 induced synapse degeneration. The synaptophysin content of cortical neurones pre-treated with a vehicle control (■), 1 μM ginkgolide B (○), 2 μM Hexa-PAF (●) or 2 μM CV6209 (□) and subsequently incubated with varying concentrations of PrP82-146 for 24 hours. Values shown are the mean average amount of synaptophysin ± SD, n = 12.
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Figure 8: PAF receptor antagonists protected against PrP82-146 induced synapse degeneration. The synaptophysin content of cortical neurones pre-treated with a vehicle control (■), 1 μM ginkgolide B (○), 2 μM Hexa-PAF (●) or 2 μM CV6209 (□) and subsequently incubated with varying concentrations of PrP82-146 for 24 hours. Values shown are the mean average amount of synaptophysin ± SD, n = 12.

Mentions: The activation of PLA2 is the first step in the production of PAF [31] that has been shown to cause synapse degeneration in vitro [27]. The addition of PAF receptor antagonists (Hexa-PAF, CV6209 or ginkgolide B), in the range 0.1-10 μM, did not affect the amount of synaptophysin in cortical neurones. However, pre-treatment with 2 μM Hexa-PAF, 2 μM CV6209 or 1 μM ginkgolide B provided protection against PrP82-146 induced synapse degeneration (Figure 8). The EC50 of PrP82-146 in vehicle treated cortical neurones was 50 nM while the EC50 of PrP82-146 for neurones treated with 2 μM Hexa-PAF was 2 μM, for neurones treated with 2 μM CV6209 the EC50 was 5 μM and for neurones pre-treated with 1 μM ginkgolide B the EC50 was 20 μM. Pre-treatment with Hexa-PAF, ginkgolide or CV6209 also prevented the reduction in the synaptophysin content of cortical neurones incubated with 100 nM Aβ1-42 or 1 μM PLAP (Table 2). In a similar manner, the amount of synaptophysin in hippocampal neurones incubated with 50 nM PrP82-146 was significantly increased by pre-treatment with 1 μM ginkgolide B (97 units synaptophysin ± 9 compared to 18 ± 7, n = 6, P < 0.01), 2 μM Hexa-PAF (94 ± 11 compared to 18 ± 7, n = 6, P < 0.01) or 2 μM CV6209 (94 ± 11 compared to 18 ± 7, n = 6, P < 0.01).


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

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

PAF receptor antagonists protected against PrP82-146 induced synapse degeneration. The synaptophysin content of cortical neurones pre-treated with a vehicle control (■), 1 μM ginkgolide B (○), 2 μM Hexa-PAF (●) or 2 μM CV6209 (□) and subsequently incubated with varying concentrations of PrP82-146 for 24 hours. Values shown are the mean average amount of synaptophysin ± SD, n = 12.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 8: PAF receptor antagonists protected against PrP82-146 induced synapse degeneration. The synaptophysin content of cortical neurones pre-treated with a vehicle control (■), 1 μM ginkgolide B (○), 2 μM Hexa-PAF (●) or 2 μM CV6209 (□) and subsequently incubated with varying concentrations of PrP82-146 for 24 hours. Values shown are the mean average amount of synaptophysin ± SD, n = 12.
Mentions: The activation of PLA2 is the first step in the production of PAF [31] that has been shown to cause synapse degeneration in vitro [27]. The addition of PAF receptor antagonists (Hexa-PAF, CV6209 or ginkgolide B), in the range 0.1-10 μM, did not affect the amount of synaptophysin in cortical neurones. However, pre-treatment with 2 μM Hexa-PAF, 2 μM CV6209 or 1 μM ginkgolide B provided protection against PrP82-146 induced synapse degeneration (Figure 8). The EC50 of PrP82-146 in vehicle treated cortical neurones was 50 nM while the EC50 of PrP82-146 for neurones treated with 2 μM Hexa-PAF was 2 μM, for neurones treated with 2 μM CV6209 the EC50 was 5 μM and for neurones pre-treated with 1 μM ginkgolide B the EC50 was 20 μM. Pre-treatment with Hexa-PAF, ginkgolide or CV6209 also prevented the reduction in the synaptophysin content of cortical neurones incubated with 100 nM Aβ1-42 or 1 μM PLAP (Table 2). In a similar manner, the amount of synaptophysin in hippocampal neurones incubated with 50 nM PrP82-146 was significantly increased by pre-treatment with 1 μM ginkgolide B (97 units synaptophysin ± 9 compared to 18 ± 7, n = 6, P < 0.01), 2 μM Hexa-PAF (94 ± 11 compared to 18 ± 7, n = 6, P < 0.01) or 2 μM CV6209 (94 ± 11 compared to 18 ± 7, n = 6, P < 0.01).

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