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

Cell Metab. 2015 Aug 4;22(2):253-65. doi: 10.1016/j.cmet.2015.05.022. Epub 2015 Jun 25.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / drug therapy
  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology
  • Animals
  • Brain / metabolism*
  • Brain / pathology
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology*
  • Memory / drug effects*
  • Mice
  • Mice, Mutant Strains
  • Nerve Growth Factors / biosynthesis*
  • Nerve Growth Factors / genetics
  • Neurons / metabolism
  • Neurons / pathology
  • PPAR alpha / genetics
  • PPAR alpha / metabolism*
  • Simvastatin / pharmacology*
  • Up-Regulation / drug effects*


  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Nerve Growth Factors
  • PPAR alpha
  • Simvastatin