| Immune/inflammatory signaling involving astrocytes is implicated as a pathway gone awry in neurodegenerative diseases including Alzheimer's disease (AD), stroke, head trauma and Parkinson's disease. The protein phosphatase calcineurin has been shown to be a major participant in immune/inflammatory signaling and participates in T-cell activation (Clipstone and Crabtree, 1992), vascular inflammation (Satonaka et al., 2004; Wilkins and Molkentin 2004), and arthritis (Magari et al., 2003). There is a remarkable increase in calcineurin expression in activated astrocytes of aged mice and mice with severe amyloidosis (Norris et al., 2005), but there is little knowledge into what calcineurin's role was in astrocytes. Moreover, transfer of activated calcineurin to rat hippocampal cultures induced "activation" like changes in astrocytes and induced numerous immune/inflammatory genes associated with astrocyte activation, brain aging and Alzheimer's disease. The results suggest that calcineurin is an important upstream regulator of immune/inflammatory signaling cascades associated with astrocyte activation. The purpose of this research project was to investigate the calcineurin signaling pathways recruited en route to the activated astrocyte phenotype and determine whether calcineurin and its related signaling molecules are changing with Alzheimer's disease. We found that inflammatory mediators trigger the activation of calcineurin in astrocytes. In turn, the activation of calcineurin turns on crucial transcription factors such as NFAT (Nuclear Factor of Activated T-cells). NFATs, once active, are known to upregulate many cytokines and inflammatory mediators, which are maintained via their continual release and bi-directional positive feedback regulation upon a single cell or an amplification event involving many cells. Using a working model (Fig. 1.1) detailing the proposed signaling events taking place during astrocyte activation, a series of experiments were performed to systematically tease apart the various facets of the calcineurin/NFAT cycle from activation of calicneurin, through release of inflammatory factors via NFAT directed transcription. Immunhistochemical characterization of the presence of calcineurin in Alzheimer's disease pathology was also performed and collaborated with data previously done in APP/PS1 mice (Norris et al 2005).; Keywords: Calcineurin, Astrocyte, Alzheimer's Disease, Inflammation, Nuclear Factor of Activated T-cells (NFATs). |
