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.

项目概要/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，通常存在的特定蛋白质 可溶性，聚集在大脑的细胞内或细胞外空间中。在 AD 中，β 淀粉样蛋白聚集。 (Aβ) 似乎启动了疾病的发病机制，并且与特定大脑区域中 tau 蛋白的聚集相关 了解导致蛋白质聚集及其扩散的因素。 特定的神经网络可能会为新疗法的开发提供重要的见解。 影响 Aβ 或 tau 聚集可能性的因素是在治疗前和头 4 年期间的浓度。 这个 PPG 项目 1 与其他 PPG 调查员合作，提供了强有力的证据表明某些事情 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 此外，影响睡眠觉醒周期的操作与增加或增加有关。 急剧减少 ISF Aβ 也会长期增加或减少 Aβ 沉积，如果这种变化发生在 虽然 tau 主要是一种胞质蛋白，但我们也发现它存在于细胞质中。 ISF 及其水平可以通过兴奋性突触活动来调节。 神经退行性疾病是某些聚集的蛋白质（例如 Aβ 和 tau）出现扩散 一旦在一个区域发生聚集，蛋白质聚集体接下来通常会出现在另一区域。 位于突触连接网络中的大脑区域在AD和动物模型中都有强有力的证据。 Aβ 聚集以某种方式驱动大脑网络内 tau 蛋白病变的进展和扩散。 在先前对睡眠/觉醒周期的研究中，蛋白质聚集体的传播可能通过类似朊病毒的机制发生。 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速 波睡眠是否对觉醒和慢波有直接的神经操纵作用？ 睡眠对 Aβ 具有相同的影响吗？ISF tau、tau 病理学和 tau 蛋白是这样的吗？ 受睡眠/觉醒周期影响的急性和慢性传播？Aβ 如何影响 ISF tau、tau？ 病理学，以及睡眠/觉醒周期变化背景下的 tau 蛋白扩散？我们欺负了 ISF Aβ？ Aβ 病理学受到睡眠觉醒周期的强烈影响，并且 Aβ 驱动 tau 蛋白病变的能力 部分通过睡眠觉醒周期影响 tau 蛋白聚集体的跨突触扩散而发生。 假设将在这些目标中得到检验：目标 1：通过直接控制慢波睡眠和觉醒。 由设计药物 (DREADD) 独家激活的设计受体并确定对 ISF 的急性影响 Aβ 和 tau 目标 2：确定通过 DREADD 和 长期调节睡眠/觉醒周期的效果。 关于 Aβ 病理学、tau 病理学、突触完整性、网络功能、睡眠和行为的其他方法 APP/PS1δE9 小鼠 +/- 人类 tau 目标 3：确定通过调节睡眠/觉醒周期的效果。 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。