title: HMG-CoA Reductase Inhibitors Bind to PPARα to Upregulate Neurotrophin Expression in the Brain and Improve Memory in Mice.
abstract: 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.
authors.affiliation: Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA.
authors.forename: Avik
authors.initials: A
authors.lastname: Roy
authors.affiliation: Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA.
authors.forename: Malabendu
authors.initials: M
authors.lastname: Jana
authors.affiliation: Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA.
authors.forename: Madhuchhanda
authors.initials: M
authors.lastname: Kundu
authors.affiliation: Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA.
authors.forename: Grant T
authors.initials: GT
authors.lastname: Corbett
authors.affiliation: Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA.
authors.forename: Suresh B
authors.initials: SB
authors.lastname: Rangaswamy
authors.affiliation: Center for Molecular Innovation and Drug Discovery, Northwestern University, Evanston, IL 60208, USA.
authors.forename: Rama K
authors.initials: RK
authors.lastname: Mishra
authors.affiliation: Weinberg College of Arts and Sciences, Northwestern University, Evanston, IL 60208, USA.
authors.forename: Chi-Hao
authors.initials: CH
authors.lastname: Luan
authors.affiliation: Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.affiliation: Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612, USA; Division of Research and Development, Jesse Brown Veterans Affairs Medical Center, 820 South Darnen Avenue, Chicago, IL 60612, USA. Electronic address: kalipada_pahan@rush.edu.
authors.forename: Kalipada
authors.initials: K
authors.lastname: Pahan
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008568:Memory / Q000187:drug effects*; D051379:Mice; D008817:Mice, Mutant Strains; D009414:Nerve Growth Factors / Q000096:biosynthesis* / Q000235:genetics; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism*; D019821:Simvastatin / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D009414:Nerve Growth Factors; D047493:PPAR alpha; D019821:Simvastatin