Aspirin binds to PPARα to stimulate hippocampal plasticity and protect memory

Proceedings of the National Academy of Sciences of the United States of America
Dhruv PatelKalipada Pahan

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.

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Citations

Jul 6, 2019·Journal of Neurochemistry·Sudipta ChakrabartiKalipada Pahan
Dec 5, 2019·Journal of Neuroscience Research·Dhruv PatelKalipada Pahan
May 24, 2019·Journal of Neuroimmune Pharmacology : the Official Journal of the Society on NeuroImmune Pharmacology·Dhruv PatelKalipada Pahan
Sep 7, 2018·Journal of Neuroimmune Pharmacology : the Official Journal of the Society on NeuroImmune Pharmacology·Suresh B RangasamyKalipada Pahan
Aug 20, 2019·Journal of Alzheimer's Disease : JAD·Sujyoti ChandraKalipada Pahan
Nov 2, 2019·Brain Sciences·Qin Xiang NgVivekanandan Sivalingam
Jun 3, 2021·Journal of Clinical Medicine·Dominika SiwikAleksandra Gąsecka
May 16, 2021·Pharmacology, Biochemistry, and Behavior·Murilo S de AbreuAllan V Kalueff
Oct 9, 2021·Seminars in Thrombosis and Hemostasis·Martin J Page, Etheresia Pretorius
Oct 27, 2021·Science Signaling·Sumita RahaKalipada Pahan

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