Adenosine Monophosphate Protein Kinase (AMPK) triggers tau hyperphosphorylation at Ser262 in response to alteration in neuronal blood supply: an implication for metabolic based hypothesis for Alzheimer’s disease

Increased tau phosphorylation (p-tau) is a causative agent of Alzheimer’s disease (AD), and a consequence of brain hypoxia. Demonstrating the effect of residues-specific tau hyperphosphorylation on cognition, leads to understanding of the pathology of memory impairment. Here we studied the cognition behaviour in a rat model of reversible cardiac arrest (CA). The activity of the main cellular metabolic axis, Liver Kinase B1 (LKB1)/Adenosine Monophosphate Kinase Protein Kinase (AMPK), along with the activity of Glycogen Synthase Kinase (GSK3β), Protein Phosphatase 2A (PP2A) and tau-specific phosphorylation at AMPK-sensitive epitope and GSK-3β- sensitive epitope were assessed in both rats and human AD brains. Our results demonstrated that LKB1/AMPK activity increased 4 weeks after CA as did AMPK specific p-tau (Ser262), however generating cognition deficits required the further involvement of GSK-3β, and PP2A, as the unchanged activity of them, along with the constant level of p-tau (Ser202/Thr205), was not associated with memory impairment. In AD brains, both AMPK and GSK-3β were activated, while PP2A showed less activity. We concluded that to create cognitive deficits, hyperphosphorylation of tau in more than one specific site and the contribution of more than one tau kinase is required.