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α-Synuclein-induced synapse damage in cultured neurons is mediated by cholesterol-sensitive activation of cytoplasmic phospholipase A2.

Bate C, Williams A - Biomolecules (2015)

Bottom Line: The accumulation of aggregated forms of the α-synuclein (αSN) is associated with the pathogenesis of Parkinson's disease (PD) and Dementia with Lewy Bodies.The loss of synapses is an important event in the pathogenesis of these diseases.They also indicate that αSN-induced activation of cPLA2 is influenced by the cholesterol content of membranes.

View Article: PubMed Central - PubMed

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

ABSTRACT
The accumulation of aggregated forms of the α-synuclein (αSN) is associated with the pathogenesis of Parkinson's disease (PD) and Dementia with Lewy Bodies. The loss of synapses is an important event in the pathogenesis of these diseases. Here we show that aggregated recombinant human αSN, but not βSN, triggered synapse damage in cultured neurons as measured by the loss of synaptic proteins. Pre-treatment with the selective cytoplasmic phospholipase A2 (cPLA2) inhibitors AACOCF3 and MAFP protected neurons against αSN-induced synapse damage. Synapse damage was associated with the αSN-induced activation of synaptic cPLA2 and the production of prostaglandin E2. The activation of cPLA2 is the first step in the generation of platelet-activating factor (PAF) and PAF receptor antagonists (ginkgolide B or Hexa-PAF) also protect neurons against αSN-induced synapse damage. αSN-induced synapse damage was also reduced in neurons pre-treated with the cholesterol synthesis inhibitor (squalestatin). These results are consistent with the hypothesis that αSN triggered synapse damage via hyperactivation of cPLA2. They also indicate that αSN-induced activation of cPLA2 is influenced by the cholesterol content of membranes. Inhibitors of this pathway that can cross the blood brain barrier may protect against the synapse damage seen during PD.

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Cyclooxygenase inhibitors protect neurons against αSN-induced synapse damage. (A) The concentrations of PGE2 produced by synaptosomes pre-treated with a vehicle control (□), cyclooxygenase inhibitors (aspirin and ibuprofen) (■) or lipoxygenase inhibitors (caffeic acid and nordihydroguaiaretic acid (NDGA)) (striped bars) and incubated with 500 nM αSN. Values are means ± SD from triplicate experiments performed three times, n = 9. * = significantly lower than control synaptosomes incubated with 500 nM αSN. The amounts of synaptophysin (B) and CSP (C) in neurons pre-treated with a vehicle control (□), cyclooxygenase inhibitors (aspirin and ibuprofen) (■) or lipoxygenase inhibitors (caffeic acid and NDGA) (striped bars) and incubated with 1 μM αSN. Values are means ± SD from triplicate experiments performed four times, n = 12. * = significantly higher than in control neurons incubated with αSN.
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biomolecules-05-00178-f003: Cyclooxygenase inhibitors protect neurons against αSN-induced synapse damage. (A) The concentrations of PGE2 produced by synaptosomes pre-treated with a vehicle control (□), cyclooxygenase inhibitors (aspirin and ibuprofen) (■) or lipoxygenase inhibitors (caffeic acid and nordihydroguaiaretic acid (NDGA)) (striped bars) and incubated with 500 nM αSN. Values are means ± SD from triplicate experiments performed three times, n = 9. * = significantly lower than control synaptosomes incubated with 500 nM αSN. The amounts of synaptophysin (B) and CSP (C) in neurons pre-treated with a vehicle control (□), cyclooxygenase inhibitors (aspirin and ibuprofen) (■) or lipoxygenase inhibitors (caffeic acid and NDGA) (striped bars) and incubated with 1 μM αSN. Values are means ± SD from triplicate experiments performed four times, n = 12. * = significantly higher than in control neurons incubated with αSN.

Mentions: Since PGE2 causes synapse degeneration [16] the effects of drugs that inhibit cyclo-oxygenases (COX), enzymes that convert arachidonic acid to prostaglandins, upon PGE2 production in synaptosomes was studied. Pre-treatment of synaptosomes with the COX inhibitors aspirin or ibuprofen significantly reduced the αSN-induced increase in PGE2 (Figure 3A). In contrast pre-treatment with drugs that inhibit lipoxygenases (LOX), enzymes that convert arachidonic acid to leucotrienes, (caffeic acid or nordihydroguaiaretic acid (NDGA)) did not affect αSN-induced increase in PGE2. Furthermore, pre-treatment of cultured neurons with aspirin or ibuprofen protected neurons against αSN-induced loss of synaptophysin (Figure 3B) or CSP (Figure 3C) whereas pre-treatment with caffeic acid or NDGA had no significant effect.


α-Synuclein-induced synapse damage in cultured neurons is mediated by cholesterol-sensitive activation of cytoplasmic phospholipase A2.

Bate C, Williams A - Biomolecules (2015)

Cyclooxygenase inhibitors protect neurons against αSN-induced synapse damage. (A) The concentrations of PGE2 produced by synaptosomes pre-treated with a vehicle control (□), cyclooxygenase inhibitors (aspirin and ibuprofen) (■) or lipoxygenase inhibitors (caffeic acid and nordihydroguaiaretic acid (NDGA)) (striped bars) and incubated with 500 nM αSN. Values are means ± SD from triplicate experiments performed three times, n = 9. * = significantly lower than control synaptosomes incubated with 500 nM αSN. The amounts of synaptophysin (B) and CSP (C) in neurons pre-treated with a vehicle control (□), cyclooxygenase inhibitors (aspirin and ibuprofen) (■) or lipoxygenase inhibitors (caffeic acid and NDGA) (striped bars) and incubated with 1 μM αSN. Values are means ± SD from triplicate experiments performed four times, n = 12. * = significantly higher than in control neurons incubated with αSN.
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biomolecules-05-00178-f003: Cyclooxygenase inhibitors protect neurons against αSN-induced synapse damage. (A) The concentrations of PGE2 produced by synaptosomes pre-treated with a vehicle control (□), cyclooxygenase inhibitors (aspirin and ibuprofen) (■) or lipoxygenase inhibitors (caffeic acid and nordihydroguaiaretic acid (NDGA)) (striped bars) and incubated with 500 nM αSN. Values are means ± SD from triplicate experiments performed three times, n = 9. * = significantly lower than control synaptosomes incubated with 500 nM αSN. The amounts of synaptophysin (B) and CSP (C) in neurons pre-treated with a vehicle control (□), cyclooxygenase inhibitors (aspirin and ibuprofen) (■) or lipoxygenase inhibitors (caffeic acid and NDGA) (striped bars) and incubated with 1 μM αSN. Values are means ± SD from triplicate experiments performed four times, n = 12. * = significantly higher than in control neurons incubated with αSN.
Mentions: Since PGE2 causes synapse degeneration [16] the effects of drugs that inhibit cyclo-oxygenases (COX), enzymes that convert arachidonic acid to prostaglandins, upon PGE2 production in synaptosomes was studied. Pre-treatment of synaptosomes with the COX inhibitors aspirin or ibuprofen significantly reduced the αSN-induced increase in PGE2 (Figure 3A). In contrast pre-treatment with drugs that inhibit lipoxygenases (LOX), enzymes that convert arachidonic acid to leucotrienes, (caffeic acid or nordihydroguaiaretic acid (NDGA)) did not affect αSN-induced increase in PGE2. Furthermore, pre-treatment of cultured neurons with aspirin or ibuprofen protected neurons against αSN-induced loss of synaptophysin (Figure 3B) or CSP (Figure 3C) whereas pre-treatment with caffeic acid or NDGA had no significant effect.

Bottom Line: The accumulation of aggregated forms of the α-synuclein (αSN) is associated with the pathogenesis of Parkinson's disease (PD) and Dementia with Lewy Bodies.The loss of synapses is an important event in the pathogenesis of these diseases.They also indicate that αSN-induced activation of cPLA2 is influenced by the cholesterol content of membranes.

View Article: PubMed Central - PubMed

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

ABSTRACT
The accumulation of aggregated forms of the α-synuclein (αSN) is associated with the pathogenesis of Parkinson's disease (PD) and Dementia with Lewy Bodies. The loss of synapses is an important event in the pathogenesis of these diseases. Here we show that aggregated recombinant human αSN, but not βSN, triggered synapse damage in cultured neurons as measured by the loss of synaptic proteins. Pre-treatment with the selective cytoplasmic phospholipase A2 (cPLA2) inhibitors AACOCF3 and MAFP protected neurons against αSN-induced synapse damage. Synapse damage was associated with the αSN-induced activation of synaptic cPLA2 and the production of prostaglandin E2. The activation of cPLA2 is the first step in the generation of platelet-activating factor (PAF) and PAF receptor antagonists (ginkgolide B or Hexa-PAF) also protect neurons against αSN-induced synapse damage. αSN-induced synapse damage was also reduced in neurons pre-treated with the cholesterol synthesis inhibitor (squalestatin). These results are consistent with the hypothesis that αSN triggered synapse damage via hyperactivation of cPLA2. They also indicate that αSN-induced activation of cPLA2 is influenced by the cholesterol content of membranes. Inhibitors of this pathway that can cross the blood brain barrier may protect against the synapse damage seen during PD.

Show MeSH
Related in: MedlinePlus