| First Author | Roy A | Year | 2015 |
| Journal | Cell Metab | Volume | 22 |
| Issue | 2 | Pages | 253-65 |
| PubMed ID | 26118928 | Mgi Jnum | J:315558 |
| Mgi Id | MGI:6829239 | Doi | 10.1016/j.cmet.2015.05.022 |
| Citation | Roy A, et al. (2015) HMG-CoA Reductase Inhibitors Bind to PPARalpha to Upregulate Neurotrophin Expression in the Brain and Improve Memory in Mice. Cell Metab 22(2):253-65 |
| abstractText | 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 PPARalpha and that Leu331 and Tyr 334 residues of PPARalpha are important for statin binding. Upon binding, statins upregulate neurotrophins via PPARalpha-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 PPARalpha, but not L331M/Y334D statin-binding domain-mutated lentiviral PPARalpha. This study identifies statins as ligands of PPARalpha, describes neurotrophic function of statins via the PPARalpha-CREB pathway, and analyzes the importance of PPARalpha in the therapeutic success of simvastatin in an animal model of Alzheimer's disease. |
