JNK3 perpetuates metabolic stress induced by Aβ peptides

Neuron. 2012 Sep 6;75(5):824-37. doi: 10.1016/j.neuron.2012.06.024.

Abstract

Although Aβ peptides are causative agents in Alzheimer's disease (AD), the underlying mechanisms are still elusive. We report that Aβ42 induces a translational block by activating AMPK, thereby inhibiting the mTOR pathway. This translational block leads to widespread ER stress, which activates JNK3. JNK3 in turn phosphorylates APP at T668, thereby facilitating its endocytosis and subsequent processing. In support, pharmacologically blocking translation results in a significant increase in Aβ42 in a JNK3-dependent manner. Thus, JNK3 activation, which is increased in human AD cases and a familial AD (FAD) mouse model, is integral to perpetuating Aβ42 production. Concomitantly, deletion of JNK3 from FAD mice results in a dramatic reduction in Aβ42 levels and overall plaque loads and increased neuronal number and improved cognition. This reveals AD as a metabolic disease that is under tight control by JNK3.

Publication types

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

MeSH terms

  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology
  • Amyloid beta-Peptides / biosynthesis
  • Amyloid beta-Peptides / metabolism*
  • Amyloid beta-Peptides / toxicity
  • Animals
  • Disease Models, Animal
  • Humans
  • Mice
  • Mice, Inbred Strains
  • Mice, Knockout
  • Mitogen-Activated Protein Kinase 10 / deficiency
  • Mitogen-Activated Protein Kinase 10 / genetics
  • Mitogen-Activated Protein Kinase 10 / metabolism*
  • Organ Culture Techniques
  • Peptide Fragments / biosynthesis
  • Peptide Fragments / metabolism*
  • Peptide Fragments / toxicity
  • Primary Cell Culture
  • Rats
  • Stress, Physiological / physiology*

Substances

  • Amyloid beta-Peptides
  • Peptide Fragments
  • amyloid beta-protein (1-42)
  • Mitogen-Activated Protein Kinase 10