Research Article

c-Jun phosphorylation in Alzheimer disease

  1. Akanksha Thakur1,
  2. Xinglong Wang1,
  3. Sandra L. Siedlak1,
  4. George Perry1,2,
  5. Mark A. Smith1,
  6. Xiongwei Zhu1,*

Article first published online: 23 APR 2007

DOI: 10.1002/jnr.21298

Issue

Journal of Neuroscience Research

Journal of Neuroscience Research

Volume 85, Issue 8, pages 1668–1673, June 2007

Additional Information

How to Cite

Thakur, A., Wang, X., Siedlak, S. L., Perry, G., Smith, M. A. and Zhu, X. (2007), c-Jun phosphorylation in Alzheimer disease. J. Neurosci. Res., 85: 1668–1673. doi: 10.1002/jnr.21298

Author Information

  1. 1

    Department of Pathology, Case Western Reserve University, Cleveland, Ohio

  2. 2

    College of Sciences, University of Texas at San Antonio, San Antonio, Texas

*Department of Pathology, Case Western Reserve University, 2103 Cornell Road, Cleveland, OH 44106

Publication History

  1. Issue published online: 18 MAY 2007
  2. Article first published online: 23 APR 2007
  3. Manuscript Accepted: 28 JAN 2007
  4. Manuscript Revised: 27 JAN 2007
  5. Manuscript Received: 16 NOV 2006

Funded by

  • National Institutes of Health. Grant Number: AG024028
  • Alzheimer's Association. Grant Number: IIRG-03-6263
  • Philip Morris USA Inc. and Philip Morris International
  • Case Western University (Source)

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Keywords:

  • Alzheimer disease;
  • cell death;
  • JNK, c-Jun;
  • oxidative stress

Abstract

The c-Jun N-terminal kinase (JNK) pathway is known to be activated by oxidative stress and can lead to either defensive-protective adaptations in the cell or apoptosis. The JNK pathway is activated in Alzheimer disease (AD), as demonstrated in studies showing higher levels of phospho-JNK in affected neurons in AD brains than in controls. c-Jun, a transcription factor, is the downstream effector of JNK, whose activation requires phosphorylation of Ser63/Ser73. In this study, we characterized and compared the localization of c-Jun phosphorylated at either Ser63 or Ser73 in the hippocampi of AD cases with that in age-matched controls. Phospho-c-Jun (Ser73) was found to be strongly associated with neurofibrillary tangles and granulovacuolar degeneration (GVD) in addition to the nuclei in neurons in the hippocampal regions of the AD brain, but was virtually absent in most controls. Phospho-c-Jun (Ser63) was also found to be associated with GVD in AD brains. Indeed, phospho-c-Jun (Ser73) immunostaining was much more extensive than that of phospho-c-Jun (Ser63), with all the phospho-c-Jun (Ser63)–positive neurons also being phospho-c-Jun (Ser73) positive. Significant overlap between phospho-c-Jun and phospho-JNK suggested a mechanistic link. In addition, the neurons showing increased levels of phospho-c-Jun (Ser73) in the cytoplasmic GVD were negative for TUNEL, suggesting a mechanism protecting the cells from death. Overall, this study demonstrated specific alterations in c-Jun phosphorylation and distribution in AD which is not necessarily linked to apoptosis but rather may represent an adaptation process in the face of oxidative stress. © 2007 Wiley-Liss, Inc.

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