Pathologic tau and dendritic spine loss in Alzheimer's disease

项目总结/摘要 阿尔茨海默病（AD）是65岁以上成年人痴呆的主要原因，目前， 影响了美国大约580万人。随着人口老龄化，预计这一数字将 到2050年增加到1380万。因此，需要在AD病因学的理解方面取得进展， 以及开发有效的治疗方法。AD的特征在于淀粉样蛋白-β（Aβ）和淀粉样蛋白的聚集体。 微管相关蛋白tau，tau病理学在整个大脑中的扩散程度与 突触丧失和认知障碍的严重程度。这个提议的目的是为了验证这个假设 磷酸化tau蛋白在突触区室中的积累有助于AD中的棘丢失。目标1将 确定AD中磷酸化tau的突触后积累是否先于树突棘损失。目标2将 确定病理性tau蛋白的跨突触扩散是否依赖于细胞朊蛋白（PrPC）的表达 在树突棘上。PrPC参与Aβ和tau诱导的突触可塑性缺陷， 作为Aβ相关的治疗药物然而，这项提案将是第一个测试阻止PrPC停止的能力的提案。 tau蛋白过度磷酸化和增殖，这两者都是AD发病机制中的关键事件。这些目标将会实现 在tau蛋白病小鼠模型和神经元培养物中通过显微镜和生物化学方法 系统.总的来说，拟议项目的发现将为病理性tau蛋白在树突棘中的作用提供信息。 损失和揭示突触tau积累和跨突触传播的机制。

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.