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

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 阿尔茨海默病、S病(AD)和其他神经退行性综合征伴随着明显的免疫/炎症反应(例如，神经胶质细胞激活和细胞因子水平升高)，这可能会导致广泛的神经元死亡和恶化。在淋巴细胞和其他类型的细胞中，钙调素依赖的蛋白磷酸酶钙调神经磷酸酶及其靶转录因子NFAT(活化T细胞的核因子)早已被认为可以诱导大量的免疫/炎症信号级联反应。因此，令人惊讶的是，钙调神经磷酸酶/NFAT通路在神经免疫/炎症信号中的类似作用没有得到广泛的研究。最近，我们发现在转基因AD模型小鼠的海马区和大脑皮层中，钙调神经磷酸酶免疫染色显著上调(Norris等，J Neurosci 25：4649,2005)。此外，在混合(神经元和神经胶质)培养的海马神经元中，激活的钙调神经磷酸酶过表达诱导了？激活样？星形胶质细胞的变化(即明显的胞体和突起肥大)，也触发了激活表型的大多数遗传标记的表达，包括许多免疫/炎症因子。结果表明，与其在淋巴细胞中众所周知的作用类似，钙调神经磷酸酶也可能是与星形胶质细胞激活和AD相关的免疫/炎症信号级联的关键上游调节因子。 利用星形胶质细胞培养和病毒介导的基因转移，这项拟议的研究将扩展我们早期的工作，确定内源性炎症介质是否在星形胶质细胞中招募钙调神经磷酸酶/NFAT途径，从而表达一组激活的星形胶质细胞表型的分子标志物。此外，编码星形胶质细胞特异性启动子的腺相关病毒将被用来确定星形胶质细胞中的钙调神经磷酸酶/NFAT活性是否对淀粉样变性AD模型小鼠的神经病理变化和认知障碍有显著影响。

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.