Does suppression of glymphatic flow explain why chronic neuropathic pain elevates the risk of developing Alzheimer-like dementia?

类淋巴液流的抑制是否可以解释为什么慢性神经性疼痛会增加患阿尔茨海默样痴呆的风险？

• 批准号: 10711478
• 负责人: Maiken Nedergaard
• 金额: $ 7.08万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10711478
• 关键词: APP-PS1; Acceleration; Acute; Acute Pain; Administrative Supplement; Age; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Amyloid; Analgesics; Anesthesia procedures; Antidepressive Agents; Antiepileptic Agents; Behavioral; Blood Vessels; Brain; Collection; Control Animal; Data; Data Collection; Dementia; Deposition; Disease; Disease Progression; Drug Interactions; Exercise; Exhibits; Experimental Designs; Failure; Goals; Grant; Histologic; Imaging Device; Impaired cognition; Individual; Inflammatory; Intervention; Light; Link; Liquid substance; Lymphatic System; Lymphatic clearance; Maps; Measures; Medical; Mind-Body Intervention; Motivation; Multimodal Imaging; Mus; Neurons; Non-Steroidal Anti-Inflammatory Agents; Norepinephrine; Omega-3 Fatty Acids; Opioid; Output; Pain; Pain Free; Pain Research; Patients; Peripheral; Pharmaceutical Preparations; Phase; Phenotype; Physiological; Population; Protein Structure Initiative; Reporting; Risk; Severities; Sleep Architecture; Stress; System; Temperature; Testing; Therapeutic; Time; United States National Institutes of Health; Wild Type Mouse; Work; aged; chronic neuropathic pain; chronic pain; cognitive ability; cognitive function; cognitive testing; cytokine; demented; experience; experimental study; fatty acid supplementation; glymphatic clearance; glymphatic dysfunction; glymphatic flow; glymphatic function; glymphatic system; improved; improvement on sleep; innovation; interest; mouse model; nerve injury; pain reduction; painful neuropathy; poor sleep; preservation; protein aggregation; response; restoration; side effect; sleep quality; spared nerve; wasting

The goal of this application for an administrative supplement for R01AT011439 is to expand ongoing studies of chronic neuropathic pain to include a murine model of Alzheimer’s disease (AD). It is known that more than 50% of patients with AD suffer from either acute or chronic pain. Pain in patients with AD is often unrecognized or undertreated, and current medical treatment can have considerable side-effects in dementia patients including adverse drug–drug interactions. Thus, an even greater need exists for identifying non-pharmacological approaches to reduce pain in patients suffering from Alzheimer disease than in the remaining population. Our underlying hypothesis is that the glymphatic system – a brain fluid transport system - sits at the crossroad of physiological and maladaptive responses to chronic neuropathic pain. We proposed that many of the classical presentations of chronic neuropathic pain are a consequence of glymphatic malfunction, including cytokine accumulation, neuronal hyperexcitability, and poor sleep quality. We are now proposing to expand the ongoing studies to include a murine model of Alzheimer disease: the APP/PSI mouse line. The proposed studies will test the hypothesis that pain induced by spared nerve injury (SNI) is more severe in the APP/PS1 mice than in age- matched controls because the glymphatic system is already suppressed. We will also test the corollary hypothesis that chronic neuropathic pain potently accelerates the loss of cognitive function and amyloid- aggregation due to the reduction of glymphatic clearance in APP/PS1 mice. We propose to systematically map the time course of chronic neuropathic pain in APP/PS1 mice and compare to age-matched controls in 4-, 8-, and 18-months old mice. We will test the following questions: Aim 1. Does suppression of glymphatic flow explain why chronic neuropathic pain elevates the risk of developing dementia? These experiments will correlate glymphatic clearance with both the severity of pain and severity of AD (cognitive test and amyloid- deposition) in 4-, 8-, and 18-month old mice APP/PS1 mice, age- matched littermate controls, and wildtype C57BL/6J mice. Aim 2. We propose that complementary interventions including omega-3 fatty acid supplementation, exercise, and improved sleep (induced by elevating temperature in the light phase) will lower baseline NE levels and improve both sleep architecture and glymphatic flow. The key endpoint of Aim 2 is to test whether the interventions preserve cognitive function in APP/PS1 mice and slow amyloid- aggregation. By collecting a large set of behavioral, physiological, and histological data in individual mice, including cytokine profile, sleep architecture, and norepinephrine levels, we will use correlation analyses will test the hypothesis that glymphatic clearance failure after SNI is the missing link explaining why neuropathic pain accelerates the progression of AD.

该应用程序为R01AT011439进行管理补充的目的是扩大对 慢性神经性疼痛包括阿尔茨海默氏病的鼠模型（AD）。众所周知，超过50％ AD患者患有急性或慢性疼痛。 AD患者的疼痛通常无法识别或 被水力不足，当前的治疗可能会在痴呆症患者中产生相当大的副作用 不良药物与药物相互作用。这是识别非药物的更大需求 减少阿尔茨海默氏病患者疼痛的方法比其余人群的疼痛方法。 我们的基本假设是，高糖基系统（一种脑流体传输系统）位于十字路口 对慢性神经性疼痛的身体和适应不良反应。我们提出了许多古典 慢性神经性疼痛的表现是糖性故障的结果，包括细胞因子 积累，神经元过度兴奋和睡眠质量差。我们现在建议扩大正在进行的 研究包括阿尔茨海默氏病的鼠模型：APP/PSI小鼠系。拟议的研究将测试 在应用程序/PS1小鼠中，由保存神经损伤（SNI）引起的疼痛（SNI）的假设比年龄 - 匹配的控件是因为已抑制了糖基系统。我们还将测试推论 慢性神经性疼痛可能会加速认知功能和淀粉样蛋白 - 的假设 由于APP/PS1小鼠的糖酶清除率的降低而导致的聚集。我们建议系统地映射 APP/PS1小鼠中慢性神经性疼痛的时间过程，并与4，8--， 和18个月的老鼠。我们将测试以下问题： 目的1。抑制糖含量流的解释说明了为什么慢性神经性疼痛升高 发展痴呆症？这些实验将与疼痛的严重程度和 4个，8个月和18个月大的小鼠APP/PS1小鼠的AD（认知测试和淀粉样蛋白沉积）的严重程度（淀粉样蛋白 - 沉积），年龄 - 匹配的同窝控制器和WildType C57BL/6J小鼠。 目标2。我们提出了互补的干预措施，包括补充欧米茄脂肪酸， 锻炼和改善的睡眠（由于光期在温度升高引起）将降低基线 NE水平并改善睡眠体系结构和糖浆流。目标2的关键终点是测试 干预措施是否保留APP/PS1小鼠的认知功能和慢速淀粉样蛋白聚集。 通过收集单个小鼠（包括细胞因子）的大量行为，物理和组织学数据 概况，睡眠结构和去甲肾上腺素水平，我们将使用相关分析将检验假设 SNI之后的糖化清除失败是缺失的链接，解释了为什么神经性疼痛加速了 AD的进展。