ROLE OF CALCINEURIN IN ASTROCYTE ACTIVATION ASSOCIATED WITH ALZHEIMER?S DISEASE

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Alzheimer?s Disease (AD) and other neurodegenerative syndromes are accompanied by a pronounced immune/inflammatory response (e.g. activated neuroglia and elevated cytokine levels) that could contribute significantly to widespread neuronal death and deterioration. In lymphocytes and other cell types, the Ca2+/calmodulin dependent protein phosphatase, calcineurin, along with its target transcription factor NFAT (nuclear factor of activated T cells) have long been recognized to induce numerous immune/inflammatory signaling cascades. As such, it is somewhat surprising that the calcineurin/NFAT pathway has not been investigated extensively for a similar role in neuro-immune/inflammatory signaling. Recently, we showed that calcineurin immunostaining is markedly upregulated in activated astrocytes in hippocampus and neocortex of transgenic AD model mice (Norris et al., J Neurosci 25:4649, 2005). Moreover, overexpression of activated calcineurin in mixed (neuronal and glial) hippocampal cultures induced ?activation-like? changes in astrocytes (i.e. pronounced hypertrophy of soma and processes) and also triggered the expression of most genetic markers for the activated phenotype, including numerous immune/inflammatory factors. The results suggest that, similar to its well-known role in lymphocytes, calcineurin also may serve as a critical upstream regulator of immune/inflammatory signaling cascades associated with astrocyte activation and AD. Using astrocyte-enriched cell cultures and viral-mediated gene transfer, the proposed research will extend our earlier work by determining whether endogenous inflammatory mediators recruit the calcineurin/NFAT pathway in astrocytes en route to the expression of a panel of molecular markers for the activated astrocyte phenotype. Furthermore, adeno-associated viruses encoding an astrocyte-specific promoter will be used to determine if calcineurin/NFAT activity in astrocytes contributes significantly to the neuropathological changes and cognitive deficits found in amyloid-bearing AD model mice.