Regional, Synaptic, Cellular Modulation of Abeta Metabolism

项目总结/摘要 阿尔茨海默病（AD）是痴呆症的最常见原因，也是一个主要的公共卫生问题。数据 来自遗传、生物化学、动物和人类的研究表明，淀粉样蛋白-β（Aβ）肽在 在启动疾病发病机制中的早期作用，微管相关蛋白tau起关键作用 神经退行性变和疾病进展。Aβ在大脑中的逐渐积累似乎 最终导致并加剧与认知能力下降和痴呆症直接相关的下游事件， 炎症和tau聚集。在这个PPG提案之前，我们发现突触和网络活动是 与脑细胞外间隙中Aβ肽的释放紧密结合，作为正常的 生物过程。我们的实验室发现了一些连接突触传递和 清醒、行为正常小鼠中Aβ水平动态变化的网络活动与人类中的确认 问题研究这一合作导致了目前的项目编制补助金的提交和供资， 从2012年4月1日到现在。我们在过去四年中取得了实质性进展。一些主要的发现是 睡眠/觉醒周期动态调节Aβ水平，Aβ释放在觉醒期间较高， 在睡眠中。这种影响，至少部分是通过清醒和睡眠之间的神经元活动差异。我们也 发现神经元的Aβ和tau蛋白释放受突触活动控制，并且可以动态监测。 还发现Aβ水平、清除和聚集可受到神经元LRP 1和LRP 2的强烈影响。 硫酸乙酰肝素蛋白聚糖（HSPG）。除了我们的发现，越来越多的证据表明，一旦关键 参与神经退行性疾病的蛋白质在大脑中聚集（例如Aβ和tau），它们似乎 在突触连接的神经元网络中从一个区域传播到其他区域。还有 越来越多的证据表明，在AD中，Aβ聚集以某种方式驱动tau蛋白病的进展和扩散。我们 我相信现在有必要进行新的研究来了解突触和网络之间的关系 活动，睡眠/觉醒周期，以及apoE/HSPG/LRP 1对Aβ，tau的影响，以及这些疾病的传播 蛋白质在大脑中聚集。这种PPG更新的总体假设是睡眠-觉醒周期和 脑网络活动调节Aβ和tau聚集以及Aβ对tau扩散的影响。我们进一步 推测apoE/LRP 1/HSPG通路影响这些作用。我们将利用创新技术， 研究这些假设的方法，如使用DREADDs，体内微透析， 微免疫电极以及各种转基因小鼠模型和病毒载体。的 这里列出了具体的项目和核心。项目1，D. Holtzman，PI：睡眠/觉醒周期对Aβ的影响， Tau和扩散。项目2，J. Cirrito，PI：Aβ和Tau构象中的神经元网络调节， 蔓延项目3，G. Bu，PI：Aβ和tau病理扩散中的神经元LRP 1和HSPG。核心A： 行政（D. Holtzman，PI）;核心B：病毒载体核心（B. J. Snider，PI）。

PROJECT SUMMARY/ABSTRACT Alzheimer's disease (AD) is the most common cause of dementia and a major public health problem. Data from genetic, biochemical, animal, and human studies suggest that the amyloid-β (Aβ) peptide plays a key early role in initiating disease pathogenesis and that the microtubule associated protein tau plays a critical role in neurodegeneration and disease progression. Progressive accumulation of Aβ in the brain appears to ultimately lead to and exacerbate downstream events directly linked to cognitive decline and dementia such as inflammation and tau aggregation. Prior to this PPG proposal, we found that synaptic and network activity is tightly coupled with the release of the Aβ peptide in the extracellular space of the brain as part of a normal biological process. Our labs discovered some of the cellular mechanisms that link synaptic transmission and network activity with dynamic changes in Aβ levels in awake, behaving mice with confirmation in human studies. This collaborative work led to the submission and funding of the current PPG which has been funded from 4/1/12 to the present. We have made substantial progress over the last 4 years. Some key findings are that the sleep/wake cycle regulates Aβ levels dynamically with Aβ release being higher during wake and lower during sleep. This effect, at least in part, is via neuronal activity differences between wake and sleep. We also found that Aβ and tau release by neurons is controlled by synaptic activity and can be monitored dynamically. It was also found that Aβ levels, clearance, and aggregation can be strongly influenced by neuronal LRP1 and heparan sulfate proteoglycans (HSPG). In addition to our findings, increasing evidence indicates that once key proteins involved in neurodegenerative diseases aggregate in the brain (e.g. Aβ and tau), they appear to spread from one region to others within neuronal networks that are synaptically connected. There is also growing evidence that in AD, Aβ aggregation in some way drives the progression and spread of tauopathy. We believe that new studies are now warranted to understand the relationship between synaptic and network activity, the sleep/wake cycle, and the impact of the apoE/HSPG/LRP1 on Aβ, tau, and the spreading of these protein aggregates in the brain. The overall hypothesis of this PPG renewal is that the sleep-wake cycle and brain network activity modulates both Aβ and tau aggregation and the effect of Aβ on tau spreading. We further hypothesize that apoE/LRP1/HSPG pathways influence these effects. We will utilize innovative techniques and approaches to study these hypotheses such as the use of DREADDs, in vivo microdialysis, and microimmunoelectrodes as well as a variety of genetically modified mouse models and viral vectors. The specific projects and Cores are listed here. Project 1, D. Holtzman, PI: Effects of the sleep/wake cycle on Aβ, tau, and spreading. Project 2, J. Cirrito, PI: Neuronal Network Regulation in Aβ and Tau Conformation and Spreading. Project 3, G. Bu, PI: Neuronal LRP1 and HSPG in pathological spreading of Aβ and tau. Core A: Administration (D. Holtzman, PI); Core B: Viral Vectors Core (B. J. Snider, PI).