Despite its long history, until now, no receptor has been identified for aspirin, one of the most widely used medicines worldwide. Here we report that peroxisome proliferator-activated receptor alpha (PPARα), a nuclear hormone receptor involved in fatty acid metabolism, serves as a receptor of aspirin. Detailed proteomic analyses including cheminformatics, thermal shift assays, and TR-FRET revealed that aspirin, but not other structural homologs, acts as a PPARα ligand through direct binding at the Tyr314 residue of the PPARα ligand-binding domain. On binding to PPARα, aspirin stimulated hippocampal plasticity via transcriptional activation of cAMP response element-binding protein (CREB). Finally, hippocampus-dependent behavioral analyses, calcium influx assays in hippocampal slices and quantification of dendritic spines demonstrated that low-dose aspirin treatment improved hippocampal plasticity and memory in FAD5X mice, but not in FAD5X/Ppara-null mice. These findings highlight a property of aspirin: stimulating hippocampal plasticity via direct interaction with PPARα.
|Original language||English (US)|
|Journal||Proceedings of the National Academy of Sciences of the United States of America|
|Early online date||Jul 16 2018|
|Publication status||Published - Jul 31 2018|
- Memory and learning
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