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

Claire Thornton (1) , Nicola J Bright , Magdalena Sastre , Phillip J Muckett , David Carling

1 Cellular Stress Group

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-related kinases, MARK and BRSK, have been implicated in tau phosphorylation but are insensitive to activation by cellular stress. Here we show that AMPK itself phosphorylates tau on a number of sites including S262 and S396, altering microtubule binding of tau. In primary mouse cortical neurons, CaMKKβ activation of AMPK in response to β-amyloid (Aβ1-42) leads to increased phosphorylation of tau at S262/S356 and S396. Activation of AMPK by Aβ1-42 is inhibited by memantine, a partial antagonist of the N-methyl-D-aspartate (NMDA) receptor and currently licensed for the treatment of Alzheimer's disease. These findings identify a pathway in which Aβ1-42 activates CaMKKβ and AMPK via the NMDA receptor suggesting the possibility that AMPK plays a role in the pathophysiological phosphorylation of tau.

Mots clés: Life Sciences

Claire Thornton, Nicola J Bright, Magdalena Sastre, Phillip J Muckett, David Carling. AMP-activated protein kinase (AMPK) is a tau kinase, activated in response to β-amyloid exposure. Biochemical Journal, 2011, 434 (3), pp.503-512. ⟨10.1042/BJ20101485⟩. ⟨hal-00569405⟩