Pathologic tau and dendritic spine loss in Alzheimer's disease

项目摘要/摘要 阿尔茨海默病(AD)是65岁以上成年人痴呆症的主要原因，目前 影响到美国约580万人。随着人口老龄化，这一数字预计将 到2050年上升到1380万。因此，有必要在理解AD病因学方面取得进展，因为 以及有效疗法的开发。AD的特征是淀粉样蛋白-β(Aβ)和 微管相关蛋白tau，以及tau病理扩散到整个大脑的程度与 突触丢失和认知障碍的严重程度。这项提议的目标是检验这一假设 这种磷酸化的tau蛋白在突触间隔室的积累导致了AD的脊椎丢失。目标1将 确定AD患者突触后磷酸化tau的积累是否先于树突棘的丢失。目标2将 病理性tau的跨突触扩散是否依赖于细胞内PrPC蛋白的表达 在树枝状刺中。PrPC参与了β和tau诱导的突触可塑性缺陷，并已被探索 作为一种与β相关的治疗药物。然而，这一提议将是第一次测试阻止PrPC停止的能力 Tau蛋白过度磷酸化和增殖是AD发病机制中的两个关键事件。这些目标将会实现 通过显微镜和生化方法在共病小鼠模型和神经元培养中的应用 系统。总体而言，拟议项目的发现将为病理性tau在树突棘中的作用提供信息。 突触tau蓄积和跨突触传播的丢失和揭示机制。

PROJECT SUMMARY/ABSTRACT Alzheimer’s disease (AD) is the leading cause of dementia in adults over the age of 65, and currently affects approximately 5.8 million people in the United States. As the population ages, this number is expected to rise to 13.8 million by the year 2050. Thus, there is a need for progress in the understanding of AD etiology, as well as in development of effective therapeutics. AD is characterized by aggregates of amyloid-β (Aβ) and of the microtubule-associated protein tau, and the extent of tau pathology spread throughout the brain correlates with both synapse loss and the severity of cognitive impairment. The goal of this proposal is to test the hypothesis that accumulation of phosphorylated tau in synaptic compartments contributes to spine loss in AD. Aim 1 will determine if postsynaptic accumulation of phosphorylated tau precedes dendritic spine loss in AD. Aim 2 will determine if trans-synaptic spread of pathologic tau is dependent on expression of the cellular prion protein (PrPC) in dendritic spines. PrPC is involved in Aβ- and tau-induced deficits in synaptic plasticity, and has been explored as an Aβ-relevant therapeutic. However, this proposal will be the first to test the ability of blocking PrPC to halt tau hyperphosphorylation and propagation, both critical events in AD pathogenesis. These aims will be achieved through both microscopy and biochemical approaches in a tauopathy mouse model and in neuronal culture systems. Overall, findings from the proposed project will inform on the role of pathologic tau in dendritic spine loss and uncover mechanisms of synaptic tau accumulation and trans-synaptic propagation.