| Abstract No.: | A-B1061 |
| Country: | Canada |
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| Title: | CALCIUM-INDEPENDENT PHOSPHOLIPASE A2 MODULATES TAU PHOSPHORYLATION AND SYNTHESIS IN HIPPOCAMPAL SLICES CULTURES FROM P301L TAU TRANSGENIC MICE |
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| Authors/Affiliations: | 1 Caroline Ménard*; 2 Guanghong Liao; 1 Guy Massicotte; 2 Xiaoning Bi;
1 UQTR, QC, Canada; 2 Western University of Health Sciences, Dallas, TX, USA
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| Content: | Over the last decade, several studies have documented that alterations in calcium-independent phospholipase A2 (iPLA2) activity were associated with the development of neurodegenerative disorders. The iPLA2 activity is significantly reduced in post-mortem brain samples from Alzheimer’s disease patients. However, the significance of this reduction in iPLA2 activity is so far unknown. Using cultured hippocampal slices from P301L tau transgenic mice, the present study examined whether iPLA2 inhibition interferes with tau hyperphosphorylation, one of the hallmarks of AD pathogenesis. Preincubation of cultured hippocampal slices with the iPLA2 inhibitor (R)-bromoenol lactone (R-BEL; 12 h, 3 µM) increased the phosphorylation of Thr231, Ser199/202 and Ser404 sites of tau proteins assayed by immunoblotting. Confocal immunofluorescence microscopy confirmed the increased phosphorylation of tau in hippocampal pyramidal neurons. Conversion of the cdk5 activator p35 to its more potent fragment, p25, was increased in iPLA2 inhibitor-treated slices, suggesting that cdk5 may participate in enhanced tau phosphorylation. Interestingly, (R)-BEL treatment also enhanced total tau expression, suggesting that tau synthesis was increased. Consistently, we observed that phosphorylation of mTor and p70S6 kinase, two enzymes implicated in proteins synthesis, was up-regulated after iPLA2 inhibition. These results thus provide the first indication that iPLA2 activity can play an important role in modulating tau phosphorylation/synthesis and raise the possibility that iPLA2 perturbation contributes to neurodegenerative processes. |
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