Cell Metabolism
Volume 22, Issue 2, 4 August 2015, Pages 253-265
Journal home page for Cell Metabolism

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

https://doi.org/10.1016/j.cmet.2015.05.022Get rights and content
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Highlights

  • 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

Summary

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.

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