Pathway of Neurotoxicity

Abstract only Two hallmarks of Alzheimer’s disease are connected through a CAMKK2-AMPK pathway. Alzheimer’s disease (AD) is a debilitating and common form of dementia and is associated with the accumulation of a cleaved fragment called Aβ (β amyloid) from the amyloid precursor protein (APP) and excessive phosphorylation of the microtubule-associated protein Tau in neurofibrillary tangles. The metabolic stress–activated kinase AMPK and its upstream activator calcium-calmodulin–dependent kinase kinase 2 (CAMKK2) is activated in neurons by Aβ peptides; in addition, AMPK phosphorylates Tau. Mairet-Coello et al . extended these findings with cultured neurons and a transgenic mouse model of AD due to the production of an APP mutant associated with human AD (APP SWE,IND ). Application of Aβ42 oligomers, which are common in amyloid plaques in AD brains, to mouse hippocampal neuron stimulated AMPK activity and reduced spine density, responses that were prevented by the addition of a CAMKK2 inhibitor. Overexpression of either CAMKK2 or subunits of AMPK or addition of a pharmacological activator of AMPK also produced a reduction in spine density. Pharmacological activation of AMPK stimulated Tau phosphorylation at the priming site, and expression of a phosphorylation-resistant mutant of Tau prevented the reduction in spine density caused by Aβ42 application to cultured hippocampal neurons. Neurons from mice deficient in AMPKα1 and CAMKK2 were resistant to the spine density–reducing effects of Aβ42. Activation of AMPK was higher and spine density was lower in hippocampal tissue from the mouse AD model than in that from control mice. The reduction in spine density in the mouse AD model was prevented by in utero electroporation of either a kinase-dead form of CAMKK2 or a kinase-dead form of AMPKα2 or by electroporation of the AMPK phosphorylation-site mutant of Tau. These results suggested that Aβ42 activates CAMKK2 to phosphorylate and activate AMPK, which phosphorylates Tau, thus connecting these two hallmarks of AD pathology through a common pathway. G. Mairet-Coello, J. Courchet, S. Pieraut, V. Courchet, A. Maximov, F. Polleux, The CAMKK2-AMPK kinase pathway mediates the synaptotoxic effects of Aβ oligomers through Tau phosphorylation. Neuron 78 , 94–108 (2013). [Online Journal]