Aspirin binds to PPAR? to stimulate hippocampal plasticity and protect memory.

ABSTRACT: 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 (PPAR?), 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 PPAR? ligand through direct binding at the Tyr314 residue of the PPAR? ligand-binding domain. On binding to PPAR?, 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 PPAR?.

SUBMITTER: Patel D 

PROVIDER: S-EPMC6077698 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature