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Ectopic expression of phospho‐Smad2 in Alzheimer's disease: Uncoupling of the transforming growth factor‐β pathway?
Author(s) -
Lee Hyounggon,
Ueda Masumi,
Zhu Xiongwei,
Perry George,
Smith Mark A.
Publication year - 2006
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.21072
Subject(s) - neuroprotection , neurodegeneration , transforming growth factor , alzheimer's disease , smad , ectopic expression , transforming growth factor beta , biology , signal transduction , pathogenesis , neuroscience , microbiology and biotechnology , medicine , disease , immunology , gene , genetics
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.