The Effects of Chronic Low Back Pain on Alzheimer's Disease Progression in a Mouse Model

项目摘要（补充项目） 在老年人中，慢性下腰痛（cLBP）经常与其他神经退行性疾病共病 包括阿尔茨海默病（AD）。据报道，AD患者慢性疼痛的患病率为45.8%， cLBP在慢性疼痛中所占比例最大。在父R 01（AR 074441）中，我们检查 晚期糖基化终产物受体对椎间盘损伤的影响 退化和腰痛。我们利用一种新的腹膜后手术技术， 并靶向损伤小鼠IVD。这种手术方法引起了退行性级联反应， 下背痛的行为症状和病理生理学特征。通过利用 亲本R 01和应用慢性下腰痛诱导的小鼠椎间盘损伤方法 阿尔茨海默病的模型，我们在一个独特的位置问这个问题：慢性腰痛是否 影响阿尔茨海默病的病理和症状发展？ 阿尔茨海默病是由淀粉样蛋白-β（Aβ）肽在脑中的进行性积累引发的， 有毒结构，如淀粉样蛋白斑和低聚物。Aβ转化为这些有毒物质似乎 是浓度依赖性的;因此，确定调节Aβ水平的机制将提供 对疾病发病机制的基本了解，从而更好地评估疾病风险， 可能会带来新的治疗策略。虽然Aβ主要在大脑中合成，但它是 通过血脑屏障双向运输。虽然一些转运蛋白将Aβ从大脑中移除， 其他的，如β-淀粉样蛋白，将Aβ从血液中转运回大脑。在小鼠中抑制A β可降低Aβ 在大脑中积累。由于cLBP中β-淀粉样蛋白升高，我们假设它也增加了Aβ 运输到大脑中，加剧Aβ病理，增加发展AD的风险。我们的研究是 还定位于研究通过抑制AD来减轻AD病理是否可以减缓 cLBP的进展 这种补充借鉴了独特的研究人员的专业知识，使新的阿尔茨海默病- 集中研究，以探索cLBP的生理学是否与AD的生理学相混淆，这将解决 未满足的临床需求。如果cLBP确实能解释AD的病理学和症状发展，那么研究结果将 激发与大部分老年人口相关的新研究方向。这项工作将有 在推进基础神经生物学的同时，对临床护理和治疗策略具有重要意义。

Project Abstract (Supplement Project) In the elderly, the chronic low back pain (cLBP) is often comorbid with other neurodegenerative disorders including Alzheimer’s Disease (AD). The reported prevalence of chronic pain in AD patients was 45.8% with cLBP accounting for the largest proportion of the chronic pain. In the parent R01 (AR074441), we examine the effects of Receptor for Advanced Glycation End-products (RAGE) on injury-induced intervertebral disc (IVD) degeneration and low back pain. We utilize a novel retroperitoneal surgical technique for the minimally invasive and targeted injury to the mouse IVD. This surgical approach invokes a degenerative cascade that leads to behavioral symptoms of low back pain and the pathophysiological hallmarks. By leveraging the studies in the parent R01 and applying the chronic low back pain inducing intervertebral disc injury approach in a mouse model of Alzheimer’s disease, we are in a unique position to ask the question: Does chronic low back pain influence the pathology and symptom development in Alzheimer’s disease? Alzheimer’s disease is initiated by the progressive accumulation of amyloid-β (Aβ) peptide in the brain as toxic structures such as amyloid plaques and oligomers. Conversion of Aβ into these toxic species appears to be concentration-dependent; therefore, identifying mechanisms that regulate Aβ levels will provide a fundamental understanding of disease pathogenesis leading to a better evaluation of disease risk and potentially lead to new therapeutic strategies. Though Aβ is synthesized primarily within the brain, it is transported bi-directionally across the blood-brain barrier. While some transporters remove Aβ from the brain, others such as RAGE, transport Aβ from blood back into the brain. Inhibition of RAGE in mice reduces Aβ accumulation within the brain. Since RAGE is elevated in cLBP, we hypothesize that it also increases Aβ transport into brain to exacerbate Aβ pathology to increase risk of developing AD. Our studies here are also positioned to investigate whether alleviating AD pathology through RAGE inhibition can slow the progression of cLBP. This supplement draws on the expertise of unique investigators to enable new Alzheimer’s disease- focused studies to explore whether the physiology of cLBP confounds with those of AD, which will address an unmet clinical need. If indeed cLBP aggravates AD pathology and symptom development, then findings will motivate new research directions relevant to a large segment of the elderly population. This work will have significant implications in clinical care and therapeutic strategies while advancing fundamental neurobiology.