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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

PrP82-146 increased activation of cPLA2 in synapses. Correlation between the amounts of activated cPLA2 in synaptosomes isolated from primary cortical neurones 1 hour after the addition of varying concentrations of PrP82-146 and the amount of synaptophysin in cell extracts from primary cortical neurones incubated for 24 hours with the same concentrations of PrP82-146.
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Figure 7: PrP82-146 increased activation of cPLA2 in synapses. Correlation between the amounts of activated cPLA2 in synaptosomes isolated from primary cortical neurones 1 hour after the addition of varying concentrations of PrP82-146 and the amount of synaptophysin in cell extracts from primary cortical neurones incubated for 24 hours with the same concentrations of PrP82-146.

Mentions: To investigate the hypothesis that synapse degeneration resulted from activation of an endogenous cPLA2, the amount of cPLA2 protein in synaptosomes was measured. The cPLA2 protein was enriched in synaptosomes isolated from cortical neurones compared to whole cell membrane extracts (100 units cPLA2/mg protein ± 31 compared to 6 units/mg ± 1, n = 12, P < 0.01). There were no significant differences in the amount of total cPLA2 protein in synaptosomes isolated from vehicle treated cortical neurones and those treated for 1 hour with 200 nM PrP82-146, 200 nM PrP82-146scrambled, 1 μM PLAP, 100 nM Aβ1-42 or 100 nM Aβ42-1 (Table 1). Measurements were made after 1 hour, before any synapse degeneration was observed. Next specific antibodies (to cPLA2 phosphorylated at serine 505) were used to determine the amount of activated cPLA2 within synaptosomes. The amount of activated cPLA2 within synaptosomes was significantly increased following the addition of 200 nM PrP82-146, 1 μM PLAP or 100 nM Aβ1-42 but not after the addition of PrP82-146scrambled or Aβ42-1 (Table 1). Moreover, there was a significant inverse correlation between the amount of activated cPLA2in synaptosomes after 1 hour and the amount of synaptophysin in neurones after 24 hours following the addition of different amounts of PrP82-146 (range 1.25 to .005 μM), Pearson's coefficient = -0.76, P < 0.01 (Figure 7).


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

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

PrP82-146 increased activation of cPLA2 in synapses. Correlation between the amounts of activated cPLA2 in synaptosomes isolated from primary cortical neurones 1 hour after the addition of varying concentrations of PrP82-146 and the amount of synaptophysin in cell extracts from primary cortical neurones incubated for 24 hours with the same concentrations of PrP82-146.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 7: PrP82-146 increased activation of cPLA2 in synapses. Correlation between the amounts of activated cPLA2 in synaptosomes isolated from primary cortical neurones 1 hour after the addition of varying concentrations of PrP82-146 and the amount of synaptophysin in cell extracts from primary cortical neurones incubated for 24 hours with the same concentrations of PrP82-146.
Mentions: To investigate the hypothesis that synapse degeneration resulted from activation of an endogenous cPLA2, the amount of cPLA2 protein in synaptosomes was measured. The cPLA2 protein was enriched in synaptosomes isolated from cortical neurones compared to whole cell membrane extracts (100 units cPLA2/mg protein ± 31 compared to 6 units/mg ± 1, n = 12, P < 0.01). There were no significant differences in the amount of total cPLA2 protein in synaptosomes isolated from vehicle treated cortical neurones and those treated for 1 hour with 200 nM PrP82-146, 200 nM PrP82-146scrambled, 1 μM PLAP, 100 nM Aβ1-42 or 100 nM Aβ42-1 (Table 1). Measurements were made after 1 hour, before any synapse degeneration was observed. Next specific antibodies (to cPLA2 phosphorylated at serine 505) were used to determine the amount of activated cPLA2 within synaptosomes. The amount of activated cPLA2 within synaptosomes was significantly increased following the addition of 200 nM PrP82-146, 1 μM PLAP or 100 nM Aβ1-42 but not after the addition of PrP82-146scrambled or Aβ42-1 (Table 1). Moreover, there was a significant inverse correlation between the amount of activated cPLA2in synaptosomes after 1 hour and the amount of synaptophysin in neurones after 24 hours following the addition of different amounts of PrP82-146 (range 1.25 to .005 μM), Pearson's coefficient = -0.76, P < 0.01 (Figure 7).

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