Calcineurin activation and scaffolding in A Beta-induced synaptic dysfunction

项目摘要 阿尔茨海默病（Alzheimer's disease，AD）是最常见的痴呆形式，随着年龄的增长，患病率不断上升 人口继续增长。在病理学上，这种神经退行性疾病的特征是淀粉样蛋白-β （Aβ）斑块和tau缠结。已证明急性应用Aβ可抑制NMDA受体（NMDAR）- 依赖性长时程增强（LTP，一种对学习和记忆至关重要的神经元可塑性的关键形式），以及 慢性Aβ暴露导致长期抑郁（LTD）和兴奋性突触消除。正常有限公司 需要蛋白磷酸酶钙调磷酸酶（CaN），对CaN的药理学抑制可防止Aβ- 介导的LTP抑制和突触丢失。但是我们不知道在哪里 神经系统的组织和结构CaN正在促进Ab的这些有害影响 突触功能在这里，我将测试新的假设，LTP抑制，兴奋性突触的损失， 与AD小鼠模型相关的认知受损是由于Aβ触发异常突触后CaN 海马锥体神经元的激活。我将进一步测试CaN是否专门本地化到 由支架蛋白AKAP 79/150介导的突触后位点负责介导这些突触毒性。 Aβ在分子、细胞和行为水平上的作用，以发现潜在的新治疗方法。 目标的

Project Summary Alzheimer’s disease (AD) is the most common form of dementia, with growing prevalence as the aging population continues to grow. Pathologically, this neurodegenerative disease is characterized by amyloid-β (Aβ) plaques and tau tangles. Acute application of Aβ has been shown to inhibit NMDA receptor (NMDAR)- dependent long-term potentiation (LTP, a key form of neuronal plasticity critical for learning and memory), and chronic Aβ exposure caused long-term depression (LTD) and elimination of excitatory synapses. Normal LTD requires the protein phosphatase Calcineurin (CaN) and pharmacological inhibition of CaN prevents Aβ- mediated LTP inhibition and synapse loss in rodent models. However, we not know where in the complex organization and architecture of the nervous system CaN is acting to promote these deleterious impacts of Ab on synaptic function. Here I will test the novel hypothesis that LTP inhibition, excitiatory synapse loss, and impaired cognition associated with mouse models of AD are due to Aβ triggering aberrant postsynaptic CaN activation in hippocampal pyramidal neurons. I will further test whether CaN that is specifically localized to postsynaptic sites by the scaffolding protein AKAP79/150 is responsible for mediating these synaptotoxic effects of Aβ at the molecular, cellular and behavioral levels in an effort to uncover potentially new therapeutic targets.