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Neuronal c-Abl overexpression leads to neuronal loss and neuroinflammation in the mouse forebrain.

Several immunocytochemical studies have revealed that Abelson tyrosine kinase (c-Abl) is associated with both neuritic plaques and neurofibrillary tangles in the brains of patients with Alzheimer's disease (AD). Additionally, c-Abl has been shown to phosphorylate tau on tyrosine 394. The activity of c-Abl is also involved in the control of the cell cycle and apoptosis. To examine the consequences of c-Abl activation in the adult brain, we have constructed two lines of transgenic mice expressing either a constitutively active form of c-Abl (AblPP/tTA mice) or its sister protein, Arg (ArgPP/tTA mice), with a neuron-specific promoter (CamKII╬▒) regulated by doxycycline (Tet-Off). Expression of active c-Abl in adult mouse forebrain neurons results in severe neurodegeneration, particularly in the CA1 region of the hippocampus. Neuronal loss was preceded and accompanied by substantial microgliosis and astrocyctosis. Despite careful examination, no c-Abl expression is found in glial cells, indicating that neuronal c-Abl expression is responsible for the gliosis. In contrast, ArgPP/tTA mice have no evidence of neuronal loss or gliosis, even though protein expression and kinase activity levels are similar to those in the AblPP/tTA mice. Given the evidence of c-Abl activation in the human AD brain combined with the pathological phenotype of AblPP/tTA mice, it is likely that aberrant c-Abl activity may play a role in neurodegenerative disease.

Pubmed ID: 21368377

Authors

  • Schlatterer SD
  • Tremblay MA
  • Acker CM
  • Davies P

Journal

Journal of Alzheimer's disease : JAD

Publication Data

August 15, 2011

Associated Grants

  • Agency: NIA NIH HHS, Id: AG022102
  • Agency: PHS HHS, Id: NIMH38623
  • Agency: NIA NIH HHS, Id: R37 AG022102
  • Agency: NIA NIH HHS, Id: R37 AG022102-09
  • Agency: NIA NIH HHS, Id: R37 AG022102-10
  • Agency: NIGMS NIH HHS, Id: T32 GM007288
  • Agency: NIGMS NIH HHS, Id: T32GM007288

Mesh Terms

  • Animals
  • CA1 Region, Hippocampal
  • Cell Count
  • Female
  • Gene Expression Regulation
  • Genes, abl
  • Inflammation
  • Male
  • Mice
  • Mice, Transgenic
  • Neurons
  • Prosencephalon
  • Pyramidal Cells