title: AMP-activated protein kinase (AMPK) is a tau kinase, activated in response to amyloid β-peptide exposure.
abstract: Hyperphosphorylation of tau is a hallmark of Alzheimer's disease and other tauopathies. Although the mechanisms underlying hyperphosphorylation are not fully understood, cellular stresses such as impaired energy metabolism are thought to influence the signalling cascade. The AMPK (AMP-activated protein kinase)-related kinases MARK (microtubule-associated protein-regulating kinase/microtubule affinity-regulating kinase) and BRSK (brain-specific kinase) have been implicated in tau phosphorylation, but are insensitive to activation by cellular stress. In the present study, we show that AMPK itself phosphorylates tau on a number of sites, including Ser²⁶² and Ser³⁹⁶, altering microtubule binding of tau. In primary mouse cortical neurons, CaMKKβ (Ca²+/calmodulin-dependent protein kinase kinase β) activation of AMPK in response to Aβ (amyloid-β peptide)-(1-42) leads to increased phosphorylation of tau at Ser²⁶²/Ser³⁵⁶ and Ser3³⁹⁶. Activation of AMPK by Aβ-(1-42) is inhibited by memantine, a partial antagonist of the NMDA (N-methyl-D-aspartate) receptor and currently licensed for the treatment of Alzheimer's disease. These findings identify a pathway in which Aβ-(1-42) activates CaMKKβ and AMPK via the NMDA receptor, suggesting the possibility that AMPK plays a role in the pathophysiological phosphorylation of tau.
authors.affiliation: Cellular Stress Group, MRC Clinical Sciences Centre, London, UK. claire.thornton@imperial.ac.uk
authors.forename: Claire
authors.initials: C
authors.lastname: Thornton
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Bright
authors.forename: Magdalena
authors.initials: M
authors.lastname: Sastre
authors.forename: Phillip J
authors.initials: PJ
authors.lastname: Muckett
authors.forename: David
authors.initials: D
authors.lastname: Carling
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000502:physiology*; D016229:Amyloid beta-Peptides / Q000494:pharmacology / Q000502:physiology*; D000818:Animals; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase / Q000235:genetics / Q000502:physiology; D020134:Catalytic Domain; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004789:Enzyme Activation; D008559:Memantine / Q000494:pharmacology; D051379:Mice; D008870:Microtubules / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology / Q000502:physiology*; D010766:Phosphorylation; D011485:Protein Binding; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D016194:Receptors, N-Methyl-D-Aspartate; C075222:amyloid beta-protein (1-42); D016875:tau Proteins; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; D055372:AMP-Activated Protein Kinases; D008559:Memantine