Neuronal c-Abl activation leads to induction of cell cycle and interferon signaling pathways
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RESEARCH
JOURNAL OF NEUROINFLAMMATION
Open Access
Neuronal c-Abl activation leads to induction of cell cycle and interferon signaling pathways Sarah D Schlatterer1, Hyeon-sook Suh1, Concepcion Conejero-Goldberg2, Shufen Chen2, Christopher M Acker1, Sunhee C Lee1 and Peter Davies1,2*
Abstract Background: Expression of active c-Abl in adult mouse forebrain neurons in the AblPP/tTA mice resulted in severe neurodegeneration, particularly in the CA1 region of the hippocampus. Neuronal loss was preceded and accompanied by substantial microgliosis and astrocytosis. In contrast, expression of constitutively active Arg (Abl-related gene) in mouse forebrain neurons (ArgPP/tTA mice) caused no detectable neuronal loss or gliosis, although protein expression and kinase activity were at similar levels to those in the AblPP/tTA mice. Methods: To begin to elucidate the mechanism of c-Abl-induced neuronal loss and gliosis, gene expression analysis of AblPP/tTA mouse forebrain prior to development of overt pathology was performed. Selected results from gene expression studies were validated with quantitative reverse transcription PCR , immunoblotting and bromodeoxyuridine (BrdU) labeling, and by immunocytochemistry. Results: Two of the top pathways upregulated in AblPP/tTA mice with c-Abl expression for 2 weeks were cell cycle and interferon signaling. However, only the expression of interferon signaling pathway genes remained elevated at 4 weeks of c-Abl induction. BrdU incorporation studies confirm that, while the cell cycle pathway is upregulated in AblPP/tTA mice at 2 weeks of c-Abl induction, the anatomical localization of the pathway is not consistent with previous pathology seen in the AblPP/tTA mice. Increased expression and activation of STAT1, a known component of interferon signaling and interferon-induced neuronal excitotoxicity, is an early consequence of c-Abl activation in AblPP/tTA mice and occurs in the CA1 region of the hippocampus, the same region that goes on to develop severe neurodegenerative pathology and neuroinflammation. Interestingly, no upregulation of gene expression of interferons themselves was detected. Conclusions: Our data suggest that the interferon signaling pathway may play a role in the pathologic processes caused by c-Abl expression in neurons, and that the AblPP/tTA mouse may be an excellent model for studying sterile inflammation and the effects of interferon signaling in the brain.
Introduction The tyrosine kinase c-Abl has been shown to co-localize with tangles, plaques, and granulovacuolar degeneration in Alzheimer’s disease (AD) [1]. The c-Abl kinase also phosphorylates tau, the amyloid precursor protein (APP) and Fe65, an adaptor protein thought to play a role in APP processing [2-6]. The c-Abl tyrosine kinase has been shown to be activated by oxidative stress and * Correspondence: [email protected] 1 Department of Pathology, Albert Einstein College of Medicine, Bronx, NY 10461, USA 2 Litwin-Zucker Center for Research in Alzheimer’s Disease and Memory Disorders, Feinstein Center for
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