Elucidating the role of AD risk factor Pyk2 in tau-induced synaptic dysfunction

项目总结 阿尔茨海默病(AD)目前在美国估计有580万人患病，这是一个数字 预计到2050年，这一数字将增长到700万。在美国，AD总体上是第六大死因， 第五大死因是65岁及以上的人。目前还没有已知的治疗疾病的方法。 为了减缓或阻止AD的进展，因此更好地了解AD的发病机制对于解决 阻碍全球健康危机。虽然据了解，淀粉样β蛋白(Aβ)会导致进行性突触丢失 并且是AD的主要贡献特征，但目前尚不清楚Aβ信号是如何触发tau病理的。 旨在揭示β是如何导致这种疾病的第二个同样重要的组成部分的研究是 危急时刻。多基因组关联研究已证实，PYK2(PTK2B)是迟发性高血压的遗传危险因素。 起病的阿尔茨海默病，占AD病例的绝大多数。PYK2都被β信号激活 它是许多Aβ相关表型的呈现所必需的，包括突触丢失和 记忆力受损。然而，我收集的初步数据表明，已经被 证实与tau直接或间接相互作用，对tau介导的神经元具有保护作用。 功能障碍。这项提案的目的将决定Pyk2如何发挥作用来保护神经元免受tau介导的影响 损害以及β如何以削弱这种保护能力的方式调节这一功能。 目的1研究Pyk2在tau介导的突触功能障碍保护神经元中的作用 和毒性。实验1a将使用电生理方法来确定Pyk2的表达 对tau介导的突触传递和可塑性损伤的保护作用已得到充分描述 颈椎病动物模型。实验1b和实验1c将确定Pyk2的表达是否调节 分别在体外和体内研究了tau相关的突触结构紊乱。 目的2将研究PYK2的S在调节β诱导的tau功能障碍中的作用及其机制 由Aβ调制。实验2a将确定PYK2的表达是否对β诱导的tau具有保护作用 人类神经元中的过度磷酸化和树突状错位。实验2b将评估Aβ如何 信号转导调控PYK2的表达和定位。实验2c将确定Pyk2蛋白如何 结合伙伴受Aβ信号的调节。 据我们所知，这些实验是理解PYK2的S在 保护突触免受tau介导的损伤，以及在Aβ存在的情况下这可能如何被干扰。 这些实验将产生关于Aβ和tau之间联系的关键信息，并可能揭示新的 未来AD治疗的蛋白质靶点。

PROJECT SUMMARY Alzheimer’s disease (AD) currently affects an estimated 5.8 million individuals in the United States, a number that is expected to grow to 7 million by 2050. In the US AD is the sixth leading cause of death overall and the fifth leading cause of death in individuals 65 and older. There are currently no disease modifying therapies known to slow or halt AD progression, thus a better understanding of AD pathogenesis is essential to address an impeding global health crisis. While it is understood that amyloid beta (Aβ) leads to progressive synapse loss and is a major contributing feature of AD, it is not well-understood how Aβ signaling triggers tau pathology. Studies designed to reveal how Aβ contributes to this second equally critical component of the disease are critical. Multiple genome wide association studies have identified Pyk2 (PTK2B) as a genetic risk factor for late- onset Alzheimer’s disease, which comprises a vast majority of AD cases. Pyk2 is both activated by Aβ signaling and is required for the presentation of a number of Aβ associated phenotypes including synapse loss and memory impairment. However, preliminary data I have gathered suggests that Pyk2, which has been demonstrated to interact both directly and indirectly with tau, is protective against tau-mediated neuronal dysfunction. The Aims of this proposal will determine how Pyk2 functions to protect neurons from tau-mediated damage and how Aβ may modulate that function in a way that diminishes this protective capacity. Aim 1 will investigate the role of Pyk2 in protecting neurons against tau-mediated synaptic dysfunction and toxicity. Experiment 1a will use an electrophysiological approach to determine whether Pyk2 expression is protective against tau-mediated impairments of synaptic transmission and plasticity in a well-described tauopathy animal model. Experiment 1b and Experiment 1c will determine whether Pyk2 expression modulates tau-associated synaptic disorganization in vitro and in vivo, respectively. Aim 2 will investigate Pyk2’s role in regulating Aβ-induced tau dysfunction and how that role is modulated by Aβ. Experiment 2a will determine whether Pyk2 expression is protective against Aβ-induced tau hyperphosphorylation and dendritic mislocalization in human neurons. Experiment 2b will assess how Aβ signaling modulates the expression and localization of Pyk2. Experiment 2c will determine how Pyk2 protein binding partners are modulated by Aβ signaling. To the best of our knowledge, these experiments represent the first attempts to understand Pyk2’s role in protecting synapses against tau-mediated damage and how that might be perturbed in the presence of Aβ. These experiments will yield critical information regarding the link between Aβ and tau and will likely reveal novel protein targets for future AD therapies.