Loss of biliverdin reductase-A favors Tau hyper-phosphorylation in Alzheimer's disease

Hyper-active GSK-3 beta favors Tau phosphorylation during the progression of Alzheimer's disease (AD). Akt is one of the main kinases inhibiting GSK-3 beta and its activation occurs in response to neurotoxic stimuli including, i.e., oxidative stress. Biliverdin reductase-A (BVR-A) is a scaffold protein favoring the Akt-mediated inhibition of GSK-3 beta. Reduced BVR-A levels along with increased oxidative stress were observed early in the hippocampus of 3xTg-AD mice (at 6 months), thus suggesting that loss of BVR-A could be a limiting factor in the oxidative stress-induced Akt-mediated inhibition of GSK-3 beta in AD. We evaluated changes of BVR-A, Akt, GSK-3 beta, oxidative stress and Tau phosphorylation levels: (a) in brain from young (6-months) and old (12-months) 3xTg-AD mice; and (b) in post-mortem inferior parietal lobule (IPL) samples from amnestic mild cognitive impairment (MCI), from AD and from age-matched controls. Furthermore, similar analyses were performed in vitro in cells lacking BVR-A and treated with H2O2. Reduced BVR-A levels along with: (a) increased oxidative stress; (b) reduced GSK-3 beta inhibition; and (c) increased Tau Ser404 phosphorylation (target of GSK-3 beta activity) without changes of Akt activation in young mice, were observed. Similar findings were obtained in MCI, consistent with the notion that this is a molecular mechanism disrupted in humans. Interestingly, cells lacking BVR-A and treated with H2O2 showed reduced GSK-3 beta inhibition and increased Tau Ser404 phosphorylation, which resulted from a defect of Akt and GSK-3 beta physical interaction. Reduced levels of Akt/GSK-3 beta complex were confirmed in both young 3xTg-AD and MCI brain. We demonstrated that loss of BVR-A impairs the neuroprotective Akt-mediated inhibition of GSK-3 beta in response to oxidative stress, thus contributing to Tau hyper-phosphorylation in early stage AD. Such changes potential provide promising therapeutic targets for this devastating disorder.