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

项目摘要/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，正常情况下 可溶的，聚集在大脑的细胞内或细胞外空间。阿尔茨海默病中淀粉样蛋白β的聚集 (aβ)似乎启动了疾病的发病机制，并且tau在特定脑区的聚集与 神经退行性变。了解导致蛋白质聚集及其传播的因素 特定的神经网络可能会为新疗法的开发提供重要的见解。一个因素 这影响了β或Tau聚集在一起的可能性是浓度。在前4年之前和之后 这个PPG，项目1，与其他PPG调查人员合作，产生了强有力的证据表明 与睡眠觉醒周期有关的调节间质液体(ISF)Aβ水平至少部分通过影响 突触活动。此外，影响睡眠唤醒周期的操作与增加或 如果发生这样的变化，ISF Aβ的急剧下降也会慢性增加或减少β的沉积 更长的时间段。虽然tau是一种主要的胞浆蛋白，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。中出现的一个关键概念 神经退行性疾病是指聚集在一起的某些蛋白质，如Aβ和tau，似乎会扩散 在大脑里。一旦在一个区域发生聚集，蛋白质聚集体通常就会出现在另一个区域 位于突触连接网络中的大脑区域。在阿尔茨海默病和动物模型中有强有力的证据 β的聚集在某种程度上推动了脑部网络中紧张症的进展和传播。这 蛋白质聚集体的扩散可能通过一种类似普里恩的机制发生。在先前对睡眠/清醒周期的研究中， 我们进行的操作不仅仅影响睡眠(例如压力)，而且不会特别影响慢 挥手睡觉。一些重要的问题仍然存在。对觉醒和慢波进行直接的神经操作 睡眠对β的影响和我们之前看到的一样吗？是ISF tau、tau病理和tau 会受到睡眠/清醒周期的剧烈和长期影响吗？β如何影响ISF，Tau 病理学，以及tau在睡眠/清醒周期变化的背景下的传播？我们假设ISF Aβ 而β的病理受到睡眠唤醒周期的强烈影响，以及β驱动牵张症的能力 部分通过影响tau聚集体跨突触扩散的睡眠觉醒周期的影响而发生。这 假说将在这些目标中得到检验。目标1：通过直接操控慢波睡眠和清醒 设计师受体被设计师药物(DREADD)特异性激活，并确定对ISF的急性影响 Aβ和Tau。目的2：确定通过DREADS和DREADS慢性调节睡眠/觉醒周期的效果 Aβ病理、tau病理、突触完整性、网络功能、睡眠和行为的其他方法 APP/PS1δE9小鼠+/-人tau。目标3：确定通过以下途径调节睡眠/清醒周期的效果 在存在和不存在Aβ的情况下，Tau扩散模型中的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.