HMG-CoA Reductase Inhibitors Bind to PPARα to Upregulate Neurotrophin Expression in the Brain and Improve Memory in Mice

Neurotrophins are important for neuronal health and function. Here, statins, inhibitors of HMG-CoA reductase and cholesterol lowering drugs, were found to stimulate expression of neurotrophins in brain cells independent of the mevalonate pathway. Time-resolved fluorescence resonance energy transfer (FRET) analyses, computer-derived simulation, site-directed mutagenesis, thermal shift assay, and de novo binding followed by electrospray ionization tandem mass spectrometry (ESI-MS) demonstrates that statins serve as ligands of PPARα and that Leu331 and Tyr 334 residues of PPARα are important for statin binding. Upon binding, statins upregulate neurotrophins via PPARα-mediated transcriptional activation of cAMP-response element binding protein (CREB). Accordingly, simvastatin increases CREB and brain-derived neurotrophic factor (BDNF) in the hippocampus of Ppara null mice receiving full-length lentiviral PPARα, but not L331M/Y334D statin-binding domain-mutated lentiviral PPARα. This study identifies statins as ligands of PPARα, describes neurotrophic function of statins via the PPARα-CREB pathway, and analyzes the importance of PPARα in the therapeutic success of simvastatin in an animal model of Alzheimer’s disease. [Display omitted] •Upregulation of neurotrophins by statins independent of the mevalonate pathway•Statins bind with Leu331 and Tyr334 residues of the ligand-binding domain of PPARα•Statins produce neurotrophins via the PPARα-CREB pathway•Simvastatin increases CREB and improves memory in an animal model of AD via PPARα Roy et al. show that the cholesterol-lowering drugs statins increase the expression of neurotrophins in the brain by binding to the ligand-binding domain of PPARα, independent of the mevalonate pathway. Simvastatin also increases neurotrophin expression and improves memory and learning in a mouse model of Alzheimer’s disease.