Wilms' tumor suppressor (WT1) is a mediator of neuronal degeneration associated with the pathogenesis of Alzheimer's disease

Mark A. Lovell, Chengsong Xie, Shuling Xiong, William R. Markesbery

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

Wilms' tumor suppressor (WT1), a 52- to 54-kda transcription factor, is the gene product of Wilms' tumor 1 (wt1), one of at least three genes involved in the development of a pediatric kidney cancer. Expression patterns of WT1 indicate that it is not restricted to the kidney but may play a role in the development and homeostasis of other tissues as well. WT1 has been implicated in various cellular processes including proliferation, differentiation, and apoptosis. High levels of WT1 induce apoptosis independent of p53, whereas low levels of WT1 inhibit apoptosis. Because apoptosis has been suggested to play a role in neurodegeneration in Alzheimer's disease (AD), immunohistochemistry of WT1 and paired helical filament (PHF) in serial sections was carried out. Immunohistochemical localization of WT1 and PHF showed the presence of WT1 in approximately 42% of PHF-positive neurofibrillary tangle containing-neurons. Laser confocal microscopy of hippocampal neuron cultures undergoing apoptosis induced by amyloid beta peptide (Aβ) or staurosporine demonstrated significant time-dependent elevations of WT1 correlating with increased levels of apoptosis. Blockade of WT1 transcription by antisense oligonucleotide reduced WT1 expression and prevented neuronal apoptosis in both Aβ- and staurosporine-treated cultures. Together, these data suggest a role for WT1 in the neurodegeneration observed in AD brain.

Original languageEnglish
Pages (from-to)84-96
Number of pages13
JournalBrain Research
Volume983
Issue number1-2
DOIs
StatePublished - Sep 5 2003

Bibliographical note

Funding Information:
The authors thank Jane Meara and Paula Thomason for technical and editorial assistance. Work was supported by National Institutes of Health grants 5P50-AG05144 and 5P01-AG05119 and by a grant from the Abercrombie Foundation.

Keywords

  • Amyloid beta peptide
  • Apoptosis
  • Neuron culture

ASJC Scopus subject areas

  • General Neuroscience
  • Molecular Biology
  • Clinical Neurology
  • Developmental Biology

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