Calcineurin activation and scaffolding in A Beta-induced synaptic dysfunction

项目摘要 阿尔茨海默病(AD)是最常见的痴呆症，随着年龄的增长，其患病率不断上升 人口继续增长。病理上，这种神经退行性疾病的特征是淀粉样蛋白-β (Aβ)斑块和牛磺酸缠结。β的急性应用被证明能抑制NMDAR- 依赖长时程增强(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A-β暴露导致长期抑郁(LTD)和兴奋性突触的消除。Normal Ltd 需要蛋白磷酸酶钙调神经磷酸酶(CaN)和CaN的药物抑制来预防Aβ- 在啮齿动物模型中介导LTP抑制和突触丢失。然而，我们不知道在建筑群的什么地方 神经系统的组织和结构正在促进抗体的这些有害影响 关于突触功能。在这里，我将测试LTP抑制、兴奋性突触丢失和 阿尔茨海默病小鼠模型相关的认知障碍是由于β触发异常的突触后CAN 海马区锥体神经元的激活。我将进一步测试是否可以将其具体定位到 突触后部位由支架蛋白AKAP79/150负责介导这些突触毒性 β在分子、细胞和行为水平上的作用，以努力发现潜在的新疗法 目标。

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.