Effects of the Sleep/Wake Cycle on A-Beta, Tau and Spreading

项目总结/摘要 在包括阿尔茨海默病（AD）在内的大多数神经退行性疾病中，通常与阿尔茨海默病（AD）相关的特异性蛋白质被激活。 可溶性的，聚集在脑的细胞内或细胞外空间。在AD中，β淀粉样蛋白的聚集 （Aβ）似乎启动疾病发病机制，并且tau蛋白在特定脑区域的聚集与 神经退化了解导致蛋白质聚集的因素及其通过 特定的神经网络将可能为开发新的治疗方法提供重要的见解。一个因素 影响Aβ或tau蛋白聚集的可能性的因素是浓度。前4年和后4年 这个PPG，项目1，与其他PPG调查人员合作，已经产生了强有力的证据，表明 与睡眠觉醒周期相关的调节间质液（ISF）Aβ水平至少部分通过影响 突触活动此外，影响睡眠觉醒周期的操作与增加或减少睡眠觉醒周期有关。 急性减少ISF Aβ也会增加或减少Aβ沉积，如果这种变化发生在 更长的时间。虽然tau蛋白主要是一种胞质蛋白，但我们也发现它存在于 它的水平可以通过兴奋性突触活动来调节。一个关键的概念出现在 神经退行性疾病的一个重要特征是某些聚集的蛋白质，如Aβ和tau蛋白， 在大脑中。一旦在一个区域发生聚集，蛋白质聚集体通常会接着出现在另一个区域 位于突触连接网络中的大脑区域。在AD和动物模型中有强有力的证据 Aβ聚集以某种方式驱动了大脑网络中tau蛋白病的进展和传播。这 蛋白质聚集体的扩散可通过朊病毒样机制发生。在之前对睡眠/觉醒周期的研究中， 我们进行了影响不仅仅是睡眠（例如压力）的操作，并且没有特别影响缓慢的睡眠。 波睡眠一些重要的问题仍然存在。对清醒和慢波的直接神经操控 睡眠对Aβ有同样的影响吗是ISF tau，tau病理学，和tau 受到睡眠/觉醒周期的急性和慢性影响？Aβ如何影响ISF tau，tau 病理学，和tau蛋白在睡眠/觉醒周期变化的背景下传播？我们假设ISF Aβ Aβ病理学受睡眠觉醒周期的强烈影响，Aβ驱动tau蛋白病的能力 部分地通过影响tau聚集体的跨突触扩散的睡眠觉醒周期的作用而发生。这 假设将在这些目标进行测试。目的1：通过以下方式直接操纵慢波睡眠和觉醒 设计者受体仅由设计者药物激活（DREADD），并确定对ISF的急性影响 Aβ和tau。目的2：确定通过DREADD长期调节睡眠/觉醒周期的影响， 其他关于Aβ病理学、tau病理学突触完整性、网络功能、睡眠和行为的方法， APP/PS1δE9小鼠+/-人tau。目的3：确定调节睡眠/觉醒周期的影响， 在存在和不存在Aβ的情况下，在tau扩散模型中使用DREADD和其他方法。

PROJECT SUMMARY/ABSTRACT In most neurodegenerative diseases including Alzheimer's disease (AD), specific proteins that are normally soluble, aggregate in either the intra- or extracellular space of the brain. In AD, the aggregation of amyloid-β (Aβ) appears to initiate disease pathogenesis and the aggregation of tau in specific brain regions is associated with neurodegeneration. Understanding factors that lead to protein aggregation and their spread through specific neural networks will likely provide important insights for development of new treatments. One factor that influences the likelihood that Aβ or tau will aggregate is concentration. Prior to and over the first 4 years of this PPG, project 1, working with the other PPG investigators, has produced strong evidence that something associated with the sleep wake cycle regulates interstitial fluid (ISF) Aβ levels at least in part via influencing synaptic activity. Further, manipulations that influence the sleep wake cycle that are linked with increasing or decreasing ISF Aβ acutely also increase or decrease Aβ deposition chronically if such changes occur over longer periods of time. While tau is a predominantly a cytosolic protein, we also found that it is present in the ISF and that its levels there can be regulated by excitatory synaptic activity. A key concept that has emerged in neurodegenerative diseases is that certain proteins that aggregate, such as Aβ and tau, appear to spread within the brain. Once aggregation occurs in one region, protein aggregates will often next appear in another brain region that is in a synaptically connected network. There is strong evidence in AD and in animal models that Aβ aggregation in some way drives the progression and spread of tauopathy within brain networks. This spread of protein aggregates may occur via a prion-like mechanism. In prior studies of the sleep/wake cycle, we performed manipulations that affect more than just sleep (e.g. stress) and did not specifically affect slow wave sleep. Some important questions remain. Does direct neural manipulation of wakefulness and slow wave sleep have the same effects we have previously seen in regard to Aβ? Is ISF tau, tau pathology, and tau spreading acutely and chronically affected by the sleep/wake cycle? How does Aβ influence ISF tau, tau pathology, and tau spreading in the context of changes in the sleep/wake cycle? We hypothesize that ISF Aβ and Aβ pathology is strongly affected by the sleep wake cycle and that the ability of Aβ to drive tauopathy occurs in part via effects of the sleep wake cycle influencing trans synaptic spread of tau aggregates. This hypothesis will be tested in these aims. Aim 1: To directly manipulate slow wave sleep and wakefulness via Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) and determine the acute effects on ISF Aβ and tau. Aim 2: To determine the effects of modulating the sleep/wake cycle chronically via DREADDs and other methods on Aβ pathology, tau pathology synaptic integrity, network function, sleep, and behavior in APP/PS1δE9 mice +/- human tau. Aim 3: To determine the effects of modulating the sleep/wake cycle via DREADDs and other methods in a tau spreading model in the presence and absence of Aβ.