Calcineurin-mediated neurodegeneration in Alzheimer Disease

该项目的重点是假设抗体引起的关键下游后果之一 钙升高是神经元中唯一的钙敏感磷酸酶钙调神经磷酸酶的激活。钙调神经磷酸酶 已知具有多种影响，从改变细胞表面神经递质的运输 转录因子NFAT激活和转录启动级联反应的受体。我们有 观察到Tg2576(APPSw)小鼠培养的神经元发生了相同类型的神经退行性变 成年TG小鼠或人类阿尔茨海默病患者树突状细胞缺失的老年斑附近的表型 棘突、树突分支的简化和神经性营养不良。这些神经元也证明了 钙的升高和钙调神经磷酸酶的激活。阻断钙调神经磷酸酶可防止这些神经退行性变 改变。此外，来自这些神经元的条件培养液导致相同的神经退行性表型。 在野生型神经元中。这可以被免疫耗竭的抗体或阻断钙调神经磷酸酶所阻断。 体内引入钙调神经磷酸酶抑制剂可改善成人斑块相关神经炎异常 转基因小鼠。在没有抗体存在的情况下，引入一种结构性活性形式的钙调神经磷酸酶足以 也会导致相同的表型。初步数据表明，NFAT的激活对这些 由于NFAT特异性抑制剂Vivit也可以阻止神经退行性变化，因此这种现象并不明显。我们的项目 将扩展这些观察以确定导致这些变化的特定类型的抗体，以检查 钙调神经磷酸酶激活导致神经退行性变的机制 批判性检验抗体诱导神经退行性变的机制是通过激活 钙调神经磷酸酶。我们将共同处于一个突出的地位，填补我们对 抗体诱导神经退变的机制。

This project focuses on the hypothesis that one of the critical downstream consequences of Ab induced calcium elevation is activation ofthe only calcium sensitive phosphatase in neurons, calcineurin. Calcineurin is known to have multiple effects, ranging from alterations in cell surface trafficking of neurotransmitter receptors to activation ofthe transcription factor NFAT and initiation of transcriptional cascades. We have observed that neurons cultured from Tg2576 (APPSw) mice develop the same sort of neurodegenerative phenotype that occur near senile plaques in the adult Tg mouse or human Alzheimer brain - loss of dendritic spines, simplification of dendritic arborizations, and neuritic dystrophies. These neurons also show evidence of elevated Calcium and activation of calcineurin. Blockade of calcineurin prevents these neurodegenerative changes. Moreover, conditioned media from these neurons leads to the same neurodegenerative phenotype in wild type neurons. This can be blocked by either immunodepletion of Ab or blockade of calcineurin. Introduction of calcineurin inhibitors in vivo improves plaque-associated neuritic abnormalities in adult transgenic mice. Introduction of a constitutively active form of calcineurin, without Ab present, is sufficient to also lead to this same phenotype. Preliminary data suggest that activation of NFAT is critical for these phenomena, since the NFAT specific inhibitor VIVIT can also block neurodegenerative changes. Our project will extend these observations to determine the specific type of Ab that induces these changes, to examine the mechanism whereby calcineurin activation leads to neurodegeneration, and to come full circle - to critically test the hypothesis that the mechanism of Ab induced neurodegeneration is via activation of calcineurin. Together we will be in an outstanding position to fill in a critical gap in our understanding ofthe mechanisms of Ab induced neurodegeneration.