| First Author | Corbett GT | Year | 2015 |
| Journal | Proc Natl Acad Sci U S A | Volume | 112 |
| Issue | 27 | Pages | 8445-50 |
| PubMed ID | 26080426 | Mgi Jnum | J:223748 |
| Mgi Id | MGI:5660152 | Doi | 10.1073/pnas.1504890112 |
| Citation | Corbett GT, et al. (2015) Activation of peroxisome proliferator-activated receptor alpha stimulates ADAM10-mediated proteolysis of APP. Proc Natl Acad Sci U S A 112(27):8445-50 |
| abstractText | Amyloid precursor protein (APP) derivative beta-amyloid (Abeta) plays an important role in the pathogenesis of Alzheimer's disease (AD). Sequential proteolysis of APP by beta-secretase and gamma-secretase generates Abeta. Conversely, the alpha-secretase "a disintegrin and metalloproteinase" 10 (ADAM10) cleaves APP within the eventual Abeta sequence and precludes Abeta generation. Therefore, up-regulation of ADAM10 represents a plausible therapeutic strategy to combat overproduction of neurotoxic Abeta. Peroxisome proliferator-activated receptor alpha (PPARalpha) is a transcription factor that regulates genes involved in fatty acid metabolism. Here, we determined that the Adam10 promoter harbors PPAR response elements; that knockdown of PPARalpha, but not PPARbeta or PPARgamma, decreases the expression of Adam10; and that lentiviral overexpression of PPARalpha restored ADAM10 expression in Ppara(-/-) neurons. Gemfibrozil, an agonist of PPARalpha, induced the recruitment of PPARalpha:retinoid x receptor alpha, but not PPARgamma coactivator 1alpha (PGC1alpha), to the Adam10 promoter in wild-type mouse hippocampal neurons and shifted APP processing toward the alpha-secretase, as determined by augmented soluble APPalpha and decreased Abeta production. Accordingly, Ppara(-/-) mice displayed elevated SDS-stable, endogenous Abeta and Abeta1-42 relative to wild-type littermates, whereas 5XFAD mice null for PPARalpha (5X/alpha(-/-)) exhibited greater cerebral Abeta load relative to 5XFAD littermates. These results identify PPARalpha as an important factor regulating neuronal ADAM10 expression and, thus, alpha-secretase proteolysis of APP. |
