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

睡眠/觉醒周期对 A-Beta、Tau 和扩散的影响

• 批准号: 10006907
• 负责人: DAVID M. HOLTZMAN
• 金额: $ 38.27万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-15 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10006907
• 关键词: Acute; Address; Affect; Alzheimer' s Disease; Amyloid beta-Protein; Animal Model; Axon; Brain; Brain region; Cell Death; Cell Nucleus; Cells; Chronic; Collaborations; Data; Designer Drugs; Development; Disease; Engineering; Extracellular Space; Functional disorder; G-Protein-Coupled Receptors; Guidelines; Heparan Sulfate Proteoglycan; Hippocampus (Brain); Human; Individual; Intercellular Fluid; Lead; Link; Metabolism; Methods; Modeling; Mus; Neocortex; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Parietal; Pathogenesis; Pathology; Process; Proteins; Research Personnel; Seeds; Sleep; Sleep Wake Cycle; Slow-Wave Sleep; Stress; Synapses; Tauopathies; Techniques; Testing; Time; Toxic effect; Viral Vector; Virus; Wakefulness; abeta accumulation; abeta deposition; beta amyloid pathology; designer receptors exclusively activated by designer drugs; entorhinal cortex; in vivo; insight; neural network; non rapid eye movement; pre-clinical; prion-like; protein aggregation; relating to nervous system; response; sleep behavior; tau Proteins; tau aggregation

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.

项目摘要/摘要 在包括阿尔茨海默氏病（AD）在内的大多数神经退行性疾病中，通常是特定蛋白 可溶性，在大脑的细胞内或细胞外空间中进行聚集。在AD中，淀粉样蛋白-β的聚集 （Aβ）似乎引发了疾病的发病机理，并且在特定大脑区域的tau聚集与 与神经变性。了解导致蛋白质聚集的因素及其通过 特定的神经网络可能会为开发新疗法提供重要的见解。一个因素 这影响了Aβ或TAU聚集的可能性是浓度。在前四年之前 该PPG项目1与其他PPG调查人员合作，已经提供了有力的证据，表明某事 与睡眠唤醒周期相关的调节间隙液（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 如果此类变化发生在 更长的时间。虽然tau主要是胞质蛋白，但我们还发现它存在于 ISF，其水平可以通过兴奋性合成活性来调节。出现的关键概念 神经退行性疾病是某些聚集的蛋白质（例如Aβ和TAU）似乎扩散 在大脑内。一旦聚集发生在一个区域中，蛋白质聚集体通常会出现在另一个区域 在突触连接网络中的大脑区域。在AD和动物模型中有强烈的证据 Aβ聚集在某种程度上驱动了双胞胎病在大脑网络中的发展和扩散。这 蛋白质聚集体的扩散可能通过类似prion的机制发生。在对睡眠/唤醒周期的先前研究中， 我们执行的操作不仅影响睡眠（例如压力），而且没有特别影响慢速 波浪睡眠。仍然存在一些重要的问题。可以直接对清醒和慢波的神经操纵 睡眠具有以前在Aβ上看到的相同影响吗？是isf tau，tau病理学和tau 受到睡眠/唤醒周期的急性和慢性影响？ Aβ如何影响iSf tau，tau 病理学，tau在睡眠/唤醒周期变化的背景下扩散？我们假设ISFAβ 和Aβ病理学受到睡眠唤醒周期的强烈影响以及Aβ驱动tauopathy的能力 部分通过睡眠唤醒周期影响tau聚集体的反式突触扩散。这 假设将在这些目标中进行检验。目标1：直接操纵慢波睡眠和通过 设计器受体专门由设计师药物（Dreadds）激活，并确定对ISF的急性影响 aβ和tau。 AIM 2：确定通过恐惧持续调节睡眠/唤醒周期的影响 有关Aβ病理学，TAU病理学突触完整性，网络功能，睡眠和行为的其他方法 App/ps1Δe9小鼠+/-人tau。目标3：确定通过调节睡眠/唤醒周期的影响 在存在和不存在Aβ的情况下，tau扩散模型中的恐惧和其他方法。