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 PPAR alpha and that Leu331 and Tyr 334 residues of PPARa are important for statin binding. Upon binding, statins upregulate neurotrophins via PPAR alpha-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 PPARa, but not L331M/Y334D statin-binding domain-mutated lentiviral PPARa. This study identifies statins as ligands of PPARa, describes neurotrophic function of statins via the PPAR alpha-CREB pathway, and analyzes the importance of PPARa in the therapeutic success of simvastatin in an animal model of Alzheimer's disease.