Biliverdin reductase-A: a novel drug target for atorvastatin in a dog pre-clinical model of Alzheimer disease

Biliverdin reductase-A (BVR-A) is a pleiotropic enzyme involved in cellular stress responses. It not only transforms biliverdin-IX alpha into the antioxidant bilirubin-IX alpha but through its serine/threonine/tyrosine kinase activity is able to modulate cell signaling networks. BVR-As involvement in neurodegenerative disorders such as Alzheimer disease (AD) and amnestic mild cognitive impairment was previously described. Statins have been proposed to reduce risk of AD. In this study we evaluated the effect of atorvastatin treatment (80 mg/day for 14.5 months) on BVR-A in the parietal cortex, cerebellum and liver of a well characterized pre-clinical model of AD, the aged beagle. We found that atorvastatin significantly increased BVR-A protein levels, phosphorylation and activity only in parietal cortex. Additionally, we found significant negative correlations between BVR-A and oxidative stress indices, as well as discrimination learning error scores. Furthermore, BVR-A up-regulation and post-translational modifications significantly correlated with beta-secretase protein levels in the brain, suggesting a possible role for BVR-A in A beta formation.