Pathologic consequences of c-Abl overexpression in mouse forebrain

Abstract

It has been shown that the Abelson tyrosine kinase (c-Abl) is associated with both neuritic plaques and neurofibrillary tangles (NFTs) in the brains of patients with Alzheimer's disease (AD) and that c-Abl phosphorylates tau, the protein comprising neurofibrillary tangles. As the c-Abl kinase has been shown to play a role in induction of the cell cycle, apoptosis, and interferon signaling in non-neuronal cells, we hypothesized that c-Abl may play a role in the pathogenesis of AD by induction of aberrant cell cycle re-entry resulting in apoptosis and interferon signaling. To examine the consequences of c-Abl activation in the adult brain, we 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 (CamKIIα) regulated by doxycycline (Tet-Off).

Expression of active c-Abl in adult mouse forebrain neurons 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, ArgPP/tTA mice showed no evidence of neuronal loss or gliosis, even though protein expression and kinase activity levels were similar to those in the AblPP/tTA mice.

Gene expression analysis of AblPP/tTA mouse forebrain prior to development of overt pathology (at 2 and 4 weeks off doxycycline) revealed upregulation of two major cell signaling pathways—cell cycle and interferon signaling. However, only the interferon signaling pathway remained elevated at 4 weeks of c-Abl induction.

We have shown that constitutive activation of c-Abl in neurons leads to neuronal loss and gliosis. This effect is c-Abl specific, as constitutive activation of Arg in forebrain neurons led to no pathological changes. Gene expression studies combined with immunohistochemistry, qPCR, and Western blotting suggest that interferon signaling is activated in neurons expressing c-Abl. Overall, this work demonstrates that c-Abl may be a significant player in neurodegenerative disease and a potential therapeutic target, as c-Abl activation alone causes neuronal death and inflammation. Additionally, the pathological phenotype resulting from c-Abl activation in neurons may relate to its ability to activate interferon signaling.