This project will investigate the effect of chronic glial activation on brain structure and function, and test the efficacy of two cytokine-suppressive anti-inflammatory drugs (CSAIDs) against chronic glial activation and the resulting neuronal damage. Activation of microglia and astroglia is a pathological process evident in many neurodegenerative diseases, including Alzheimer’s disease. The currently used anti-inflammatory drugs such as NSIADs and corticosteroids have shown limited effects in many neuroinflammatory diseases. Consequently, it has been suggested that drugs targeting neuroinflammation such as CSAIDs might yield disease-modifying treatments for these neurodegenerative disorders.
We will explore the GFAP-IL6 mouse, in which chronic neuroinflammation is induced by astroglia-specific production of interleukin 6 (IL6). We will use a variety of behavioural tests to monitor motor skills and cognitive functions in these mice up to 24 months of age. Furthermore, the anti-inflammatory effects of two CSAIDs (curcumin and apigenin) will be tested in this model, first in a dose-response study, and then in prevention and a treatment studies. In the diagnostic/imaging arm of our study, we will investigate whether chronic neuroinflammation can be detected in our mouse model using a PET tracer for the 18 kDa translocator protein (TSPO), a marker of activated microglia. This will allow us to follow the success of treatment of neuroinflammation by CSAID in the live mouse.
Methods: Techniques involved will be immunohistochemistry, stereology, 3D reconstruction using MBF Neurolucida/Stereoinvestigator and/or behavioural analysis. Previous experience with these techniques are an advantage.