Editors' ChoicePharmacology

Repurposing statins for Alzheimer’s disease

Sci. Signal.  11 Aug 2015:
Vol. 8, Issue 389, pp. ec223
DOI: 10.1126/scisignal.aad2049

Statins are drugs that inhibit the enzyme HMG-coA reductase in the mevalonate pathway to lower cholesterol and suppress inflammation. Roy et al. found that statins additionally induce the production of neurotrophins that improve memory in mice but do so through a mechanism independent of the cholesterol-lowering and anti-inflammatory effects. In cultured mouse and human astrocytes and microglia, various statins induced the expression of genes encoding the neurotrophins BDNF and NT-3. Pretreating cultured astrocytes with increasing concentrations of metabolites in the mevalonate pathway did not abrogate the neurotrophin-inducing effects of simvastatin, and inhibiting the mevalonate pathway through RNA interference or the expression of dominant-negative mutants of key pathway enzymes did not induce neurotrophin abundance, although each had the expected effects on inflammatory markers. Simvastatin increased the abundance of all three isoforms (α, β, and γ) of the peroxisome proliferator–activated receptor (PPAR) and the activity of a reporter containing a PPAR-response element (PPRE), but only astrocytes lacking PPARα failed to show BDNF and NT-3 induction after simvastatin exposure. In contrast, simvastatin induced the HMG-coA reductase inhibition–mediated anti-inflammatory effects in astrocytes lacking PPARα. Simvastatin increased the abundance of BDNF in the cortex of wild-type but not Pppara-null mice. As predicted by in silico docking models and confirmed by mass spectrometry–based pulldown, time-resolved fluorescence resonance, and site-directed mutagenesis studies in cultured mouse astrocytes, statins bound two amino acids in the ligand-binding domain of PPARα, and this interaction was required for simvastatin-induced increase in the abundance of BDNF and NT-3. The promoters for BDNF and NTF3 (encoding NT-3) did not contain PPRE; however, both contained cAMP response element-binding protein (CREB)-response element (CRE) sequences, and the promoter for CREB contained PPRE sequences. Accordingly, statins induced the recruitment of PPARα to the CREB promoter and, hence, the expression of CREB in wild-type but not Ppara-null microglia and astrocytes in culture and in the cortex of wild-type but not Ppara-null mice. Knocking down CREB in cultured mouse astrocytes inhibited the increase in BDNF and NT-3 by simvastatin. Simvastatins improved memory associated with a maze performance in both wild-type mice and a transgenic mouse model of Alzheimer’s disease, but not in mice lackingPPARα. The findings reveal a new mode of action for statins and suggest that they may help improve memory in Alzheimer’s patients.

A. Roy, M. Jana, M. Kundu, G. T. Corbett, S. B. Rangaswamy, R. K. Mishra, C.-H. Luan, F. J. Gonzalez, K. Pahan, HMG-CoA reductase inhibitors bind to PPARα to upregulate neurotrophin expression in the brain and improve memory in mice. Cell Metab. 22, 253–265 (2015). [PubMed]