Calcineurin-mediated neurodegeneration in Alzheimer Disease

该项目的重点是假设一个关键的下游后果的抗体诱导 钙升高是激活神经元中唯一的钙敏感磷酸酶，钙调神经磷酸酶。钙调 已知具有多种效应，从改变细胞表面神经递质的运输， 受体激活转录因子NFAT和启动转录级联反应。我们有 观察到从Tg 2576（APPSw）小鼠培养的神经元发生了相同类型的神经退行性病变， 在成年Tg小鼠或人阿尔茨海默病脑中老年斑附近发生的表型-树突状细胞的缺失 棘、树突分支的简化和神经炎性营养不良。这些神经元也显示出 高钙和钙调神经磷酸酶的激活。阻断钙调神经磷酸酶可以防止这些神经退行性疾病 变化此外，来自这些神经元的条件培养基导致相同的神经退行性表型 在野生型神经元中。这可以通过抗体的免疫耗竭或钙调磷酸酶的阻断来阻断。 钙调神经磷酸酶抑制剂在体内的引入改善了成人斑块相关神经炎异常 转基因小鼠在不存在Ab的情况下，引入钙调磷酸酶的组成型活性形式足以 也会导致同样的表型。初步数据表明，NFAT的激活对于这些疾病的发生至关重要。 这是因为NFAT特异性抑制剂VIVIT也可以阻断神经退行性变化。我们的项目 我将扩展这些观察，以确定诱导这些变化的特定类型的抗体， 钙调神经磷酸酶激活导致神经退行性变的机制， 严格检验Ab诱导神经变性的机制是通过激活 钙调神经磷酸酶我们将共同处于一个突出的地位，以填补我们对世界和平的理解方面的一个关键空白。 Ab诱导神经退行性变的机制。

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.