Chronic pain is linked to cognitive impairment; however, the underlying mechanisms remain unclear. In the present study, we examined these mechanisms in a well-established mouse model of Alzheimer’s disease (AD). Neuropathic pain was modeled in 5-month-old transgenic APPswe/PS1dE9 (APP/PS1) mice by partial ligation of the sciatic nerve on the left side, and chronic inflammatory pain was modeled in another group of APP/PS1 mice by injecting them with complete Freund’s adjuvant on the plantar surface of the left hind paw. Six weeks after molding, the animals were tested to assess pain threshold (von Frey filament), learning, memory (novel object recognition, Morris water maze, Y-maze, and passive avoidance), and depression-like symptoms (sucrose preference, tail suspension, and forced swimming). After behavioral testing, mice were sacrificed and the levels of p65, amyloid-β (residues 1–42) and phospho-tau in the hippocampus and cerebral cortex were assayed using western blotting, while interleukin (IL)-1β levels were measured by enzyme-linked immunosorbent assay. Animals subjected to either type of chronic pain showed lower pain thresholds, more severe deficits in learning and memory, and stronger depression-like symptoms than the corresponding control animals. Either type of chronic pain was associated with upregulation of p65, amyloid-β (1–42), and IL‐1β in the hippocampus and cerebral cortex, as well as higher levels of phosphorylated tau. Chronic pain may exacerbate cognitive deficits and depression-like symptoms in APP/PS1 mice by worsening pathology related to amyloid-β and tau and by upregulating signaling involving IL-1β and p65.

中文翻译：

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在阿尔茨海默病小鼠模型中，慢性疼痛通过上调 IL-1β 和 p-65 信号传导加剧记忆障碍以及 Aβ 和 tau 蛋白病理学

慢性疼痛与认知障碍有关；然而，其根本机制仍不清楚。在本研究中，我们在成熟的阿尔茨海默病（AD）小鼠模型中检查了这些机制。通过部分结扎左侧坐骨神经，在 5 个月大的转基因 APPswe/PS1dE9 (APP/PS1) 小鼠中建立神经病理性疼痛模型；在另一组 APP/PS1 小鼠中通过注射将完全弗氏佐剂涂在左后爪的足底表面上。成型六周后，对动物进行测试，评估疼痛阈值（冯弗雷丝）、学习、记忆（新物体识别、莫里斯水迷宫、Y 迷宫和被动回避）和抑郁样症状（蔗糖偏好、尾巴暂停和强迫游泳）。行为测试后，处死小鼠，使用蛋白质印迹法测定海马和大脑皮层中 p65、淀粉样蛋白-β（残基 1-42）和磷酸 tau 的水平，同时通过酶测定白细胞介素 (IL)-1β 水平连锁免疫吸附测定。与相应的对照动物相比，遭受任何一种慢性疼痛的动物都表现出较低的疼痛阈值、更严重的学习和记忆缺陷以及更强的抑郁样症状。这两种类型的慢性疼痛都与海马和大脑皮层中 p65、淀粉样蛋白-β (1-42) 和 IL-1β 的上调以及磷酸化 tau 蛋白的升高有关。慢性疼痛可能会恶化 APP/PS1 小鼠的认知缺陷和抑郁样症状，原因是与淀粉样蛋白-β 和 tau 蛋白相关的病理恶化，以及涉及 IL-1β 和 p65 的信号传导上调。