The CAMKK2-AMPK Kinase Pathway Mediates the Synaptotoxic Effects of Aβ Oligomers through Tau Phosphorylation

• Published in: Neuron (Cambridge, Mass.) Mass.), 2013-04, Vol.78 (1), p.94-108
• Main Authors: Mairet-Coello, Georges, Courchet, Julien, Pieraut, Simon, Courchet, Virginie, Maximov, Anton, Polleux, Franck
• Format: Article
• Language: English
• Subjects: Action Potentials - drug effects; Action Potentials - genetics; Amyloid beta-Peptides - toxicity; Amyloid beta-Protein Precursor - genetics; Animals; Brain - cytology; Calcium - metabolism; Calcium-Calmodulin-Dependent Protein Kinase Kinase - metabolism; Cells, Cultured; Dendritic Spines - drug effects; Dendritic Spines - genetics; Dose-Response Relationship, Drug; Electroporation; Embryo, Mammalian; Enzyme Inhibitors - pharmacology; Gene Expression Regulation, Enzymologic - drug effects; Gene Expression Regulation, Enzymologic - genetics; Glutamic Acid - pharmacology; Green Fluorescent Proteins - genetics; Humans; Life Sciences; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mutation - genetics; Neurobiology; Neurons - drug effects; Neurons - physiology; Neurons - ultrastructure; Neurons and Cognition; Patch-Clamp Techniques; Peptide Fragments - toxicity; Phosphorylation - drug effects; Platelet-Derived Growth Factor - genetics; Protein Kinases - metabolism; Serine - metabolism; tau Proteins - metabolism; Transfection
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2013.02.003

Amyloid-β 1–42 (Aβ42) oligomers are synaptotoxic for excitatory cortical and hippocampal neurons and might play a role in early stages of Alzheimer’s disease (AD) progression. Recent results suggested that Aβ42 oligomers trigger activation of AMP-activated kinase (AMPK), and its activation is increased in the brain of patients with AD. We show that increased intracellular calcium [Ca2+]i induced by NMDA receptor activation or membrane depolarization activates AMPK in a CAMKK2-dependent manner. CAMKK2 or AMPK overactivation is sufficient to induce dendritic spine loss. Conversely, inhibiting their activity protects hippocampal neurons against synaptotoxic effects of Aβ42 oligomers in vitro and against the loss of dendritic spines observed in the human APPSWE,IND-expressing transgenic mouse model in vivo. AMPK phosphorylates Tau on KxGS motif S262, and expression of Tau S262A inhibits the synaptotoxic effects of Aβ42 oligomers. Our results identify a CAMKK2-AMPK-Tau pathway as a critical mediator of the synaptotoxic effects of Aβ42 oligomers. ► Aβ oligomers activate AMPK in a CAMKK2-dependent manner ► Blocking CAMKK2 and AMPK function protects neurons from synaptotoxic effects of Aβ ► AMPK phosphorylates Tau on S262 ► Expression of Tau S262A protects neurons from synaptotoxic effects of Aβ Mairet-Coello et al. demonstrate that the CAMKK2-AMPK kinase pathway mediates the synaptotoxic effects of Ab42 oligomers in hippocampal neurons. These effects are mediated through the ability of AMPK to phosphorylate Tau on Serine 262.