AMP-activated protein kinase (AMPK) is a tau kinase, activated in response to amyloid β-peptide exposure.

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 Ser(262) and Ser(396), altering microtubule binding of tau. In primary mouse cortical neurons, CaMKK beta (Ca(2+)/calmodulin-dependent protein kinase kinase beta) activation of AMPK in response to A beta (amyloid-beta peptide)- (1-42) leads to increased phosphorylation of tau at Ser(262)/Ser(356) and Ser(396). Activation of AMPK by A beta-(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 A beta-(1-42) activates CaMKK beta and AMPK via the NMDA receptor, suggesting the possibility that AMPK plays a role in the pathophysiological phosphorylation of tau.