Early Glycogen Synthase Kinase-3β (GSK-3β) and Protein Phosphatase 2A (PP2A) independent tau dephosphorylation during global brain ischemia and reperfusion following cardiac arrest and the role of the Adenosine Monophosphate Kinase (AMPK) pathway

Abstract

Abnormal tau phosphorylation (p-tau) has been shown after hypoxic damage to the brain associated with traumatic brain injury and stroke. As the level of p-tau is controlled by Glycogen Synthase Kinase (GSK)-3β, Protein Phosphatase 2A (PP2A) and Adenosine Monophosphate Kinase (AMPK), different activity levels of these enzymes could be involved in tau phosphorylation following ischemia. This study assessed the effects of global brain ischemia/reperfusion on the immediate status of p-tau in a rat model of cardiac arrest (CA) followed by cardiopulmonary resuscitation (CPR). We reported an early dephosphorylation of tau at its AMPK sensitive residues, Ser³⁹⁶ and Ser²⁶²after 2 min of ischemia, which did not recover during up to two hours of reperfusion, while the tau phosphorylation at GSK-3β sensitive but AMPK insensitive residues, Ser²⁰²/Thr²⁰⁵ (AT8), as well as the total amount of tau remained unchanged. Our data showed no alteration in the activities of GSK-3β and PP2A during similar episodes of ischemia of up to 8 min and reperfusion of up to 2 hours, and 4 weeks recovery.

Dephosphorylation of AMPK followed the same pattern as tau dephosphorylation during ischemia/reperfusion. Catalase, another AMPK downstream substrate also showed a similar pattern of decline to p-AMPK, in ischemic/reperfusion groups. This suggests the involvement of AMPK in changing the p-tau levels, indicating that tau dephosphorylation following ischemia is not dependent on GSK-3β or PP2A activity, but is associated with AMPK dephosphorylation. We propose that a reduction of AMPK activity is a possible early mechanism responsible for tau dephosphorylation.

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