Early glycogen synthase kinase‐3β and protein phosphatase 2A independent tau dephosphorylation during global brain ischaemia and reperfusion following cardiac arrest and the role of the adenosine monophosphate kinase pathway. (8th June 2016)

• Record Type: Journal Article
• Authors: Majd, Shohreh; Power, John H. T.; Koblar, Simon A.; Grantham, Hugh J. M.
• Editors: Bolam, Paul
• Is Part Of: European journal of neuroscience. Volume 44:Number 3(2016:Aug.)
• Page Start: 1987
• Page End: 1997
• Publication Date: 2016-06-08
• Subjects: adenosine monophosphate kinase protein -- glycogen synthase kinase‐3β -- microtubule‐associated protein -- neuronal energy stress -- phosphorylation -- protein phosphatase 2A; Nervous system -- Periodicals; 612.8
• DOI: 10.1111/ejn.13277
• Languages: English
• ISSNs: 0953-816X

Abstract

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 ischaemia. This study assessed the effects of global brain ischaemia/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, Ser 396 and Ser 262 after 2 min of ischaemia, which did not recover during the first two hours of reperfusion, while the tau phosphorylation at GSK‐3β sensitive but AMPK insensitive residues, Ser 202 /Thr 205 (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 ischaemia of up to 8 min and reperfusion of up to 2 h, and 4 weeks recovery. Dephosphorylation of AMPK followed the same pattern as tau dephosphorylation during ischaemia/reperfusion. Catalase, another AMPK downstream substrate also showed a similar pattern of decline to p‐AMPK, in ischaemic/reperfusion groups. This suggests the involvement of AMPK in changing the p‐tau levels, indicating that tau dephosphorylation following ischaemia is not dependent on GSK‐3β or PP2A activity, but is associated with AMPK dephosphorylation. We propose that a reduction in AMPK activity is a possible early mechanism responsible for tau dephosphorylation. Abstract : This study suggests that AMPK, as the most likely neuronal metabolic sensor plays a major role in altering tau phosphorylation in early stages of ischaemia. Reduction in AMPK activity plays the dominant role in reducing tau phosphorylation as the immediate response to ischaemic stress, with the possible benefit of saving ATP until energy production can be restored. This event suggests the important roles for AMPK in tau phosphorylation, especially in response to changes in brain metabolism.