Inhibition of c-Jun kinase provides neuroprotection in a model of Alzheimer's disease

Neurobiol Dis. 2010 Sep;39(3):311-7. doi: 10.1016/j.nbd.2010.04.015. Epub 2010 May 6.


The c-Jun N-terminal kinase (JNK) pathway potentially links together the three major pathological hallmarks of Alzheimer's disease (AD): development of amyloid plaques, neurofibrillary tangles, and brain atrophy. As activation of the JNK pathway has been observed in amyloid models of AD in association with peri-plaque regions and neuritic dystrophy, as we confirm here for Tg2576/PS(M146L) transgenic mice, we directly tested whether JNK inhibition could provide neuroprotection in a novel brain slice model for amyloid precursor protein (APP)-induced neurodegeneration. We found that APP/amyloid beta (Abeta)-induced neurodegeneration is blocked by both small molecule and peptide inhibitors of JNK, and provide evidence that this neuroprotection occurs downstream of APP/Abeta production and processing. Our findings demonstrate that Abeta can induce neurodegeneration, at least in part, through the JNK pathway and suggest that inhibition of JNK may be of therapeutic utility in the treatment of AD.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology
  • Amyloid beta-Peptides / metabolism
  • Amyloid beta-Protein Precursor / metabolism
  • Analysis of Variance
  • Animals
  • Blotting, Western
  • Brain / metabolism*
  • Brain / pathology
  • Disease Models, Animal
  • JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors*
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Mice
  • Mice, Transgenic
  • Nerve Degeneration / metabolism
  • Nerve Degeneration / pathology
  • Nerve Degeneration / prevention & control*
  • Neurofibrillary Tangles / metabolism
  • Neurofibrillary Tangles / pathology
  • Neurons / metabolism*
  • Neurons / pathology
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction


  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • JNK Mitogen-Activated Protein Kinases