LOSS OF BILIVERDIN REDUCTASE-A FAVORS TAU HYPERPHOSPHORYLATION IN ALZHEIMER DISEASE

Abstract

Hyper-active GSK-3β favors Tau phosphorylation during the progression of Alzheimer disease (AD). Akt is one of the main kinases inhibiting GSK-3β 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-3β. Interestingly, 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-3β in AD and would favor increased Tau hyperphosphorylation. We evaluated changes of BVR-A, Akt, GSK-3β, oxidative stress and Tau phosphorylation levels (1) in young (6-months) and old (12-months) 3xTg-AD mice; and (2) in post-mortem inferior parietal lobule (IPL) samples from MCI, AD and age-matched controls. Furthermore, similar analyses were performed in vitro in HEK cells lacking BVR-A and treated with H2O2. Reduced BVR-A levels along with (1) increased oxidative stress; (2) reduced GSK-3β inhibition and (3) increased Tau Ser404 (target of GSK-3β activity) phosphorylation without changes of Akt activation both in young mice and in MCI, were observed. Interestingly, cells lacking BVR-A and treated with H2O2 showed reduced GSK-3β inhibition and increased Tau Ser404 phosphorylation, which resulted from a defect of Akt and GSK-3β physical interaction. Furthermore, reduced levels of Akt/GSK-3β complex were confirmed in the hippocampus of young 3xTg-AD mice and human MCI brain. In our study we demonstrate that loss of BVR-A impairs the neuroprotective Akt-mediated inhibition of GSK-3β in response to oxidative stress, thus contributing to Tau hyper-phosphorylation in early stage AD. This molecular mechanism shed a light on involvement of BVR-A as a scaffold in Tauopathy at early AD progression.