The CAMKK2-AMPK kinase pathway mediates the synaptotoxic effects of Aβ oligomers through Tau phosphorylation

Neuron. 2013 Apr 10;78(1):94-108. doi: 10.1016/j.neuron.2013.02.003.

Abstract

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 APP(SWE,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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mutation / genetics
  • Neurons / drug effects
  • Neurons / physiology*
  • Neurons / ultrastructure
  • Patch-Clamp Techniques
  • Peptide Fragments / toxicity*
  • Phosphorylation / drug effects
  • Platelet-Derived Growth Factor / genetics
  • Protein Kinases / metabolism*
  • Serine / metabolism
  • Transfection
  • tau Proteins / metabolism*

Substances

  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Enzyme Inhibitors
  • Peptide Fragments
  • Platelet-Derived Growth Factor
  • amyloid beta-protein (1-42)
  • platelet-derived growth factor A
  • tau Proteins
  • Green Fluorescent Proteins
  • Glutamic Acid
  • Serine
  • Protein Kinases
  • AMP-activated protein kinase kinase
  • Calcium-Calmodulin-Dependent Protein Kinase Kinase
  • Camkk2 protein, mouse
  • Calcium