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

Research output: Contribution to journalArticle

4 Citations (Scopus)

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
StatePublished - Jul 31 2018

Fingerprint

PPAR alpha
Aspirin
Ligands
Cyclic AMP Response Element-Binding Protein
Dendritic Spines
Cytoplasmic and Nuclear Receptors
Proteomics
Transcriptional Activation
Hippocampus
Fatty Acids
Hot Temperature
History
Calcium

Keywords

  • Aspirin
  • Memory and learning
  • Plasticity
  • PPARα

ASJC Scopus subject areas

  • General

Cite this

Patel, Dhruv ; Roy, Avik ; Kundu, Madhuchhanda ; Jana, Malabendu ; Luan, Chi Hao ; Gonzalez, Frank J. ; Pahan, Kalipada. / Aspirin binds to PPARα to stimulate hippocampal plasticity and protect memory. In: Proceedings of the National Academy of Sciences of the United States of America. 2018 ; Vol. 115, No. 31. pp. E7408-E7417.
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Aspirin binds to PPARα to stimulate hippocampal plasticity and protect memory. / Patel, Dhruv; Roy, Avik; Kundu, Madhuchhanda; Jana, Malabendu; Luan, Chi Hao; Gonzalez, Frank J.; Pahan, Kalipada.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 115, No. 31, 31.07.2018, p. E7408-E7417.

Research output: Contribution to journalArticle

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AU - Patel, Dhruv

AU - Roy, Avik

AU - Kundu, Madhuchhanda

AU - Jana, Malabendu

AU - Luan, Chi Hao

AU - Gonzalez, Frank J.

AU - Pahan, Kalipada

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