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的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 老年痴呆症？阿尔茨海默病（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，活化的神经胶质细胞和升高的细胞因子水平），其可显著促进广泛的神经元死亡和退化。在淋巴细胞和其他细胞类型中，Ca 2 +/钙调蛋白依赖性蛋白磷酸酶，钙调磷酸酶，沿着其靶转录因子NFAT（活化T细胞的核因子）长期以来被认为诱导许多免疫/炎症信号级联。 因此，有些令人惊讶的是，钙调磷酸酶/NFAT途径尚未被广泛研究在神经免疫/炎症信号传导中的类似作用。最近，我们显示钙调磷酸酶免疫染色在转基因AD模型小鼠的海马和新皮质中的活化星形胶质细胞中显著上调（Norris等人，J Neurosci 25：4649，2005）。此外，激活的钙调磷酸酶在混合（神经元和神经胶质）海马培养诱导？类似激活星形胶质细胞的变化（即索马和突起的显著肥大），并且还触发了活化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，类似于其在淋巴细胞中的众所周知的作用，钙调神经磷酸酶也可以作为与星形胶质细胞活化和AD相关的免疫/炎症信号级联的关键上游调节剂。 使用星形胶质细胞富集的细胞培养物和病毒介导的基因转移，拟议的研究将通过确定内源性炎症介质是否在星形胶质细胞中招募钙调磷酸酶/NFAT通路来表达活化星形胶质细胞表型的一组分子标志物来扩展我们早期的工作。此外，将使用编码星形胶质细胞特异性启动子的腺相关病毒来确定星形胶质细胞中的钙调神经磷酸酶/NFAT活性是否显著促进在携带淀粉样蛋白的AD模型小鼠中发现的神经病理学变化和认知缺陷。

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.