Aspirin binds to PPARα to stimulate hippocampal plasticity and protect memory

Dhruv Patel, Avik Roy, Madhuchhanda Kundu, Malabendu Jana, Chi Hao Luan, Frank J. Gonzalez, Kalipada Pahan*

*Corresponding author for this work

Research output: Contribution to journalArticle

10 Scopus citations

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 (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 languageEnglish (US)
Pages (from-to)E7408-E7417
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number31
Early online dateJul 16 2018
DOIs
Publication statusPublished - Jul 31 2018

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Keywords

  • Aspirin
  • Memory and learning
  • Plasticity
  • PPARα

ASJC Scopus subject areas

  • General

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