Neuronal c-Abl activation leads to induction of cell cycle and interferon signaling pathways

Sarah D Schlatterer,Peter Davies,Christopher M Acker,Shufen Chen,Hyeon-Sook Suh,Concepcion Conejero-Goldberg,Sunhee C Lee

doi:10.1186/1742-2094-9-208

Abstract

BackgroundExpression 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.MethodsTo 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.ResultsTwo 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.ConclusionsOur 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.

Highlights

The tyrosine kinase c-Abl has been shown to co-localize with tangles, plaques, and granulovacuolar degeneration in Alzheimer’s disease (AD) [1]
We show the anatomic location of the induction of cell cycle and interferon stimulated genes in the AblPP/tTA mouse brain, and that changes in interferon-stimulated gene expression occurred in neurons and co-localized in the CA1 region of the hippocampus, which was previously shown to develop severe neuronal loss and neuroinflammation
Cell cycle activation in the AblPP/tTA mouse Genes in the cell cycle pathway were strongly upregulated in AblPP/tTA mouse forebrain at 2 weeks off doxycyline, but no significant upregulation was present for any of the cell cycle-related genes at 4 weeks off doxycyline

Summary

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 tyrosine kinase has been shown to be activated by oxidative stress and treatment with Aβ peptides in neurons in culture [7]. These known activators of c-Abl are associated with aging and AD and, together with data showing c-Abl activation and co-localization with the characteristic lesions of AD, suggest that c-Abl may be activated during aging and neurodegenerative disease. The AblPP/tTA mouse develops progressive neurodegeneration and neuroinflammation in the CA1 region of the hippocampus, indicating that activation of c-Abl alone in adult neurons is sufficient to cause neuronal loss and inflammation [8]. Expression of constitutively active Arg (Abl-related gene) in mouse forebrain neurons (ArgPP/tTA mice) caused no detectable neuronal loss or gliosis, protein expression and kinase activity were at similar levels to those in the AblPP/tTA mice

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Results

Conclusion