“Despite its long history, until now, no receptor has been identified for aspirin, one of the most widely used medicines worldwide.” Here Patel and colleagues report that peroxisome proliferator-activated receptor alpha (PPARα), a nuclear hormone receptor involved in fatty acid metabolism, serves as a receptor of aspirin. Detailed analyses 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). Low-dose aspirin also improved hippocampal function in an animal model of Alzheimer’s disease via PPARα. These results delineate a new receptor of aspirin through which it may protect memory and learning.
Patel D, Roy A, Kundu M, Jana M, Luan C-H, Gonzalez FJ, and Pahan K: Aspirin binds to PPARα to stimulate hippocampal plasticity and protect memory. Proc. Natl. Acad. Sci. USA 115 (31): E7408-E7417 (2018).