Roy A, Jana M, Kundu M, Corbett GT, Rangaswamy SB, Mishra RK, Luan CH, Gonzalez FJ, Pahan K. 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. Epub 2015 Jun 25 PubMed.
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Indiana University School of Medicine
This recent publication by Roy et al. reports a novel, non-canonical action of statins in the brain, whereby they stimulate the nuclear receptor PPARα. There has been considerable controversy over the pleiotrophic actions of the statins, in particular as they relate to Alzheimer’s disease. There is reasonable epidemiological evidence demonstrating a reduction in AD risk with sustained statin use. There was no clear linkage of these finding to suppression of cholesterol levels in the central nervous system. Clinical trials of statins, either in therapeutic or preventive AD trials, have failed. This manuscript brings together several disparate threads of research and potentially adds some clarity to the actions of the statins in the brain.
Importantly, Roy and colleagues have clearly established that stains bind to and activate the nuclear receptor PPARα in multiple cell types in the brain. Interestingly, the statins bind PPARαthrough interactions within the ligand-binding domain that differ from those employed by highly specific, synthetic PPARα agonists. There have been numerous reports of statins interacting with all PPARs, most frequently PPARγ. Here, the authors nicely demonstrate statin specificity for PPARα. The dissection of these interactions is impressive. However, there are several unanswered questions. For example, it is entirely unclear if statins drive the expression of canonical PPARα-regulated genes, and this would seem to be an important positive control bolstering their conclusion that statins act to activate PPARα.
Statins previously have been reported to induce the expression of neurotrophins, and the present study adds mechanistic clarity to this phenomenon. A striking finding is that induction of neurotrophin expression relies upon PPARa-driven CREB expression. These data nicely sync with their previous work. They report a PPAR response element (PPRE) in the promoter of the CREB gene, however, there are several consensus PPRE sequences that are specific for the individual PPAR receptors and it is unclear if the sequence they found conforms to that of PPARα.
Despite extensive investigation of statin actions in murine models of AD, there has been little support for their attenuation of disease pathogenesis in such models, particularly when it comes to improving behavior. Here, the authors report a significant improvement in spatial memory in statin-treated 5XFAD mice using the Barnes maze. This is not a typical test in this transgenic line, but the data are persuasive.
In summary, this is an important contribution to understanding the breadth of statin actions in the brain, with clear therapeutic implications.
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