Aspirin binds to PPARa to stimulate hippocampal plasticity and protect memory

作者：Patel Dhruv; Roy Avik; Kundu Madhuchhanda; Jana Malabendu; Luan Chi Hao; Gonzalez Frank J; Pahan Kalipada^*

来源：Proceedings of the National Academy of Sciences of the United States of America, 2018, 115(31): E7408-E7417.

DOI：10.1073/pnas.1802021115

• aspirin
• PPARa
• plasticity
• memory and learning

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 alpha), 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 alpha ligand through direct binding at the Tyr314 residue of the PPAR alpha ligand-binding domain. On binding to PPAR alpha, 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 alpha.

• 出版日期2018-7-31
• 单位NIH; 西北大学