The first two authors contributed equally to this work.
Ectopic expression of phospho-Smad2 in Alzheimer's disease: Uncoupling of the transforming growth factor-β pathway?
Version of Record online: 22 SEP 2006
Copyright © 2006 Wiley-Liss, Inc.
Journal of Neuroscience Research
Volume 84, Issue 8, pages 1856–1861, December 2006
How to Cite
Lee, H.-g., Ueda, M., Zhu, X., Perry, G. and Smith, M. A. (2006), Ectopic expression of phospho-Smad2 in Alzheimer's disease: Uncoupling of the transforming growth factor-β pathway?. J. Neurosci. Res., 84: 1856–1861. doi: 10.1002/jnr.21072
- Issue online: 15 NOV 2006
- Version of Record online: 22 SEP 2006
- Manuscript Accepted: 28 JUL 2006
- Manuscript Revised: 18 MAY 2006
- Manuscript Received: 24 FEB 2006
- National Institutes of Health
- Alzheimer's Association
- Philip Morris USA, Inc.
- Philip Morris International
- Alzheimer's disease;
- granular vacuolar degeneration;
- neurofibrillary tangles;
- signal transduction;
- transforming growth factor-β
Transforming growth factor-β (TGF-β), a multifunctional cytokine, has been widely suggested to play a role in the pathogenesis of Alzheimer's disease. Supporting this, levels of TGF-β are elevated in the cerebrospinal fluid, sera, and brain of patients with Alzheimer's disease. Since TGF-β is neuroprotective, whereas Alzheimer's disease is typified by neurodegeneration, we speculated that defects in TGF-β signaling might abrogate its neuroprotective properties. Consistently with an increase in TGF-β in Alzheimer's disease, we found significant increases in phospho-Smad2, a major downstream signaling molecule of TGF-β, in hippocampal neurons of Alzheimer's disease compared with age-matched control patients. However, in contrast to an expected nuclear localization, phosphorylated Smad2 in Alzheimer's disease was predominantly, and ectopically, found in the neuronal cytoplasm, specifically colocalized with neurofibrillary tangles and granulovacuolar degeneration. Given that a nuclear localization is required to regulate the transcription of TGF-β target genes to afford neuroprotection, the ectopic localization of phosphorylated Smad2 suggests a defect in the Smad-mediated signaling pathway of TGF-β in Alzheimer's disease and consequent loss of neuroprotective function. © 2006 Wiley-Liss, Inc.