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

R 01 AT 011439管理补充申请的目的是扩展正在进行的研究， 慢性神经性疼痛包括阿尔茨海默病（AD）的鼠模型。据了解，超过50%的 的AD患者患有急性或慢性疼痛。AD患者的疼痛通常无法识别， 治疗不足，目前的药物治疗可能对痴呆症患者产生相当大的副作用， 药物间的不良相互作用因此，更需要鉴定非药理学的 与其他人群相比，阿尔茨海默病患者的疼痛减轻方法。 我们的基本假设是，胶质淋巴系统--一种脑液运输系统--位于 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胶质淋巴功能障碍的结果，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的鼠模型：APP/PSI小鼠系。拟议的研究将测试 假设在APP/PS1小鼠中由备用神经损伤（SNI）诱导的疼痛比年龄更严重， 与对照组相匹配，因为胶质淋巴系统已经被抑制。我们还将检验推论 慢性神经性疼痛可能加速认知功能和淀粉样蛋白的丧失 在APP/PS1小鼠中，由于胶质淋巴清除率的降低而导致的聚集。我们建议系统地绘制 在APP/PS1小鼠中慢性神经性疼痛的时间过程，并与4-，8-， 和18个月大的老鼠我们将测试以下问题： 目标1。胶质淋巴流的抑制是否可以解释为什么慢性神经性疼痛会增加 发展成痴呆症这些实验将使胶质淋巴清除与疼痛的严重程度和 在4、8和18月龄的APP/PS1小鼠中AD的严重程度（认知测试和淀粉样蛋白沉积）， 匹配的同窝对照和野生型C57 BL/6 J小鼠。 目标2.我们建议补充干预措施，包括补充欧米茄-3脂肪酸， 运动和改善睡眠（由在光照阶段升高温度引起）将降低基线 NE水平和改善睡眠结构和胶质淋巴流动。目标2的关键终点是测试 干预是否保留APP/PS1小鼠的认知功能和减缓淀粉样蛋白聚集。 通过收集单个小鼠的大量行为、生理和组织学数据，包括细胞因子， 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后胶质淋巴清除功能障碍是解释为什么神经性疼痛会加速 AD的进展。

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.