The impairment of BVR-A favors the oxidative stress-mediated uncoupling of the Akt/GSK-3b axis in Alzheimer's disease and diabetes

Hyper-active GSK-3b favors Tau phosphorylation in Alzheimer's disease (AD) and inhibits glycogen synthase in type 2 diabetes (T2DM). Akt normally inhibits GSK-3b and this process is mediated by biliverdin reductase-A (BVR-A), that works as scaffold protein. Since we demonstrated that BVR-A is a stress sensor and its early impairment occurs during insulin resistance (IR), we investigated the cross-talk with GSK-3b activity. Changes of BVR-A, Akt, GSK-3b levels/activation along with changes of oxidative stress levels and Tau phosphorylation were evaluated in (1) 3xTg-AD mice hippocampus before (6 M) and after (12 M) the development of brain IR and (2) in peripheral cells from T2DM subjects and their matched controls. To confirm data collected in vivo, ad hoc experiments in HEK cells silenced for BVR-A were performed. We found that reduced BVR-A levels are associated with (1) increased oxidative stress levels and (2) the uncoupling of Akt/GSK-3b axis both in AD and T2DM. The role of BVR-A was confirmed in vitro by showing that oxidative stress leads to Akt-mediated inactivation of GSK-3b in control HEK cells, but promotes the uncoupling of Akt/GSK-3b axis in cells lacking BVR-A. These results unravel a novel pathological mechanism favoring GSK-3b hyper-activation both in AD and T2DM.