Calcineurin Mediates the Synergistic Toxicity of Tau and Aβ Oligomers

项目总结/摘要 阿尔茨海默病（Alzheimer's disease，AD）是我国老年人最常见、最严重的神经退行性痴呆。 无法治愈的时期功能障碍的靶向毒性寡聚体诱导的突触功能障碍 Ab和Tau（AD中的两种标志性淀粉样蛋白）被认为是AD中最早的事件之一， 初期认知能力下降和临床表现。防止这种寡聚体破坏突触的作用， 从而成为AD的有效和综合治疗，阻断A β和B β的联合驱动毒性， τ的然而，实现这一重要目标的战略仍然难以捉摸。在本项目中，我们希望解决 这一关键的知识差距，通过测试的假设，激活钙调磷酸酶（CN）介导的 A β和tau寡聚体对突触协同作用。CN是一种富含CNS的磷酸酶， 参与突触功能和记忆形成。AD患者脑内CN活性异常增高 以及AD的tg小鼠模型，以及用FK 506（FDA批准的免疫抑制剂）抑制CN 药物）保护突触免受A β寡聚体的影响，并在转基因AD小鼠模型中恢复记忆。最值得注意的是， 我们发现，长期接受FK506治疗的实体器官移植受者的AD发生率是 与普通人群相比，这一比例大幅下降。根据最近的证据，这是非常重要的 显示hTau的过表达诱导CNS中CN升高，并且tau寡聚体诱导突触突触连接。 缺陷和记忆功能障碍的协同作用与A β寡聚体，强烈表明这两个物种的冲击， 基于共同的分子靶点介导它们在AD发作和临床进展中的组合关键作用。我们 提出这种共同的靶点是CN，CN抑制是阻断 导致AD的tau和A β寡聚体的联合毒性。在本项目中，将采用体外，离体 以及体内模型和尸检人脑标本来机械地测试我们的假设， CN在介导tau寡聚体的破坏性作用中的作用（Aim 1），并通过建立CN作为常见的 介导tau和Ab寡聚体对突触和记忆功能的组合协同影响的靶点 (Aim 2）。在完成拟议的研究时，我们将记录下以前未被重视的作用， CN作为标志AD的两种淀粉样蛋白的毒性寡聚体的分子会聚点 神经病理学、tau和A β的研究，并说明了FK506在预防其联合毒性中的有益作用。 考虑到FK506（FDA批准的药物）的转化价值，这一发现将在以下方面产生重大影响： 通过促进AD创新治疗概念的发展， 阻断tau和A β毒性物质，这是一种预期在人类中有效的策略， 长期接受FK506治疗的移植患者对AD的恢复力。

PROJECT SUMMARY/ABSTRACT Alzheimer’s disease (AD) is the most common and severe age-associated neurodegenerative dementia of our times for which there is no cure. Synaptic dysfunction induced by the dysfunctional targeting toxic oligomers of both Ab and Tau (the two hallmark amyloids in AD) is recognized as one of the earliest events in AD, driving initial cognitive decline and clinical manifestation. Preventing such oligomer disrupting action on synapses would thus be an effective and comprehensive therapy for AD, blocking the combined driving toxicity of both A and tau. However, a strategy to achieve this important goal remains elusive. In the present project we wish to address this critical knowledge gap by testing the hypothesis that activation of calcineurin (CN) mediates the synergistic effect of A and tau oligomers on synapses. CN is a CNS-abundant phosphatase critically involved in synaptic function and memory formation. CN activity is abnormally increased the brain of AD patients as well as tg mouse models of AD, and inhibition of CN with FK506 (an FDA-approved immunosuppressant drug) protects synapses from A oligomers and restores memory in transgenic AD mouse models. Most notably, we showed that the incidence of AD in solid organ transplant recipients chronically treated with FK506 is dramatically reduced as compared to the general population. This is highly significant in light of recent evidence showing that overexpression of hTau induces elevated CN in the CNS, and that tau oligomers induce synaptic deficits and memory dysfunction in synergy with A oligomers, strongly suggesting that the two species impinge upon a common molecular target mediating their combined key role in AD onset and clinical progression. We propose that such common target is CN and that CN inhibition is an effective approach to block the combined toxicity of tau and A oligomers that drive AD. In the present project will employ in vitro, ex vivo and in vivo models and autopsy human brain specimens to mechanistically test our hypothesis by characterizing the role of CN in mediating the disruptive effects of tau oligomers (Aim 1) and by establishing CN as the common target mediating the combined, synergistic impact of tau and Ab oligomers on synaptic and memory function (Aim 2). At the completion of the proposed studies we will have documented a previously unappreciated role of CN as the point of molecular convergence of the toxic oligomers of the two amyloid proteins that hallmark AD neuropathology, tau and A, and illustrated the beneficial effects of FK506 in preventing their combined toxicity. Given the translational value of FK506 (an FDA-approved drug) this discovery will have a substantial impact in the field by promoting the development of an innovative treatment concept for AD centered on simultaneous blockade of tau and A toxic species, a strategy expected to be effective in humans as suggested by the resilience to AD of transplanted patients chronically treated with FK506.