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.

本 R01AT011439 行政补充申请的目的是扩大正在进行的研究 慢性神经性疼痛，包括阿尔茨海默病（AD）小鼠模型。据了解，超过50% 的 AD 患者患有急性或慢性疼痛。 AD 患者的疼痛常常未被识别或 治疗不足，目前的药物治疗可能会对痴呆症患者产生相当大的副作用，包括 不良药物相互作用。因此，更需要识别非药理学 与其他人群相比，减轻阿尔茨海默病患者疼痛的方法。 我们的基本假设是类淋巴系统（脑液运输系统）位于十字路口 对慢性神经性疼痛的生理和适应不良反应。我们提出许多经典的 慢性神经性疼痛的表现是类淋巴系统功能障碍的结果，包括细胞因子 累积、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病小鼠模型：APP/PSI 小鼠系。拟议的研究将测试 假设 APP/PS1 小鼠中由幸存神经损伤 (SNI) 引起的疼痛比同龄小鼠更严重 匹配对照，因为类淋巴系统已经被抑制。我们还将测试推论 假设慢性神经性疼痛会加速认知功能和淀粉样蛋白-的丧失 由于 APP/PS1 小鼠的类淋巴清除率降低而导致聚集。我们建议系统地绘制地图 APP/PS1 小鼠慢性神经性疼痛的时间进程，并与 4-、8-、 和 18 个月大的小鼠。我们将测试以下问题： 目标 1. 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以下风险： 发展为痴呆症？这些实验将把类淋巴清除率与疼痛的严重程度和 4、8 和 18 月龄小鼠 APP/PS1 小鼠 AD 的严重程度（认知测试和淀粉样蛋白-β 沉积），年龄 匹配的同窝对照小鼠和野生型 C57BL/6J 小鼠。 目标 2. 我们建议补充干预措施，包括补充 omega-3 脂肪酸、 锻炼和改善睡眠（由浅阶段温度升高引起）将降低基线 NE 水平并改善睡眠结构和类淋巴液流动。目标 2 的关键终点是测试 这些干预措施是否可以保留 APP/PS1 小鼠的认知功能并减缓淀粉样蛋白- 的聚集。 通过收集个体小鼠的大量行为、生理和组织学数据，包括细胞因子 概况、睡眠结构和去甲肾上腺素水平，我们将使用相关性分析来检验假设 SNI 后的类淋巴清除失败是解释为什么神经性疼痛会加速 AD 的进展。