Yang Cui-Cui, Jia Xiao-Yu, Zhang Li, Li Ya-Li, Zhang Zhan-Jun, Li Lin, Zhang Lan
Department of Pharmacy, Xuanwu Hospital of Capital Medical University, Beijing Institute for Brain Disorders, Beijing Engineering Research Center for Nerve System Drugs, Key Laboratory for Neurodegenerative Diseases of Ministry of Education, Beijing 100053, China.
State Key Laboratory of Cognitive Neuroscience and Learning & IDG/McGovern Institute for Brain Research, Beijing Normal University, Beijing 100875, China.
Chin Herb Med. 2020 Oct 6;12(4):421-429. doi: 10.1016/j.chmed.2020.04.005. eCollection 2020 Oct.
Alzheimer's disease (AD) is along with cognitive decline due to amyloid-β (Aβ) plaques, tau hyperphosphorylation, and neuron loss. Shenqi Xingnao Granules (SQXN), a traditional Chinese medicine, significantly ameliorated the cognitive function and daily living abilities of patients with AD. However, till date, no study has investigated the mechanism of action of SQXN on AD. The present study aimed to verify the effects of SQXN treatment on cognitive impairments and AD-like pathologies in APP/PS1 mice.
Four-month-old APP/PS1 transgenic (Tg) mice were randomly divided into a model group and SQXN-treated (3.5, 7, 14 g/kg per day) groups. Learning-memory abilities were determined by Morris water maze and object recognition test. All mice were sacrificed and the brain samples were collected after 75 d. The soluble Aβ contents were detected by Elisa kit; The levels of expression of NeuN, APP, phosphorylated tau and related protein were measured by Western blotting; The inflammation factors were detected by the proinflammatory panel kit.
Four-month-old APP/PS1 mice were administered SQXN by oral gavage for 2.5 months. Using the Morris water maze tests and Novel object recognition, we found that SQXN restored behavioral deficits in the experimental group of Tg mice when compared with the controls. SQXN also inhibited neuronal loss (NeuN marker). SQXN treatment decreased soluble Aβ42 through inhibiting the expression of sAPPβ and BACE-1 without regulating full-length amyloid precursor protein (FL APP). Insulin degrading enzyme (IDE), the Aβ degrading enzyme, were increased by SQXN. In addition, SQXN reduced hyperphosphorylated tau protein levels and prevented excessive activation of p-GSK-3β in the brain of APP/PS1 mice. Compared with APP/PS1 transgenic negative mice, IFN-γ, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-12p70, KC/GRO and TNF-α were not obviously changed in the brain of 6.5-month-old APP/PS1 transgenic (Tg) mice. However, SQXN could inhibited the expression of IL-2.
These results demonstrate that SQXN ameliorates the cognitive impairments in APP/PS1 mice. The possible mechanisms involve its inhibition of neuronal loss, soluble Aβ deposition, tau hyperphosphorylation and inflammation.
阿尔茨海默病（AD）伴随因β-淀粉样蛋白（Aβ）斑块、tau蛋白过度磷酸化和神经元丢失导致的认知功能衰退。中药参芪醒脑颗粒（SQXN）能显著改善AD患者的认知功能和日常生活能力。然而，迄今为止，尚无研究探讨SQXN对AD的作用机制。本研究旨在验证SQXN治疗对APP/PS1小鼠认知障碍和AD样病理变化的影响。
将4月龄的APP/PS1转基因（Tg）小鼠随机分为模型组和SQXN治疗组（每天3.5、7、14 g/kg）。通过莫里斯水迷宫和物体识别试验测定学习记忆能力。75天后处死所有小鼠并采集脑样本。用酶联免疫吸附测定试剂盒检测可溶性Aβ含量；用蛋白质免疫印迹法检测NeuN、APP、磷酸化tau蛋白及相关蛋白的表达水平；用促炎因子检测试剂盒检测炎症因子。
对4月龄APP/PS1小鼠进行2.5个月的灌胃给予SQXN处理。通过莫里斯水迷宫试验和新物体识别试验，我们发现与对照组相比，SQXN可改善Tg小鼠实验组的行为缺陷。SQXN还可抑制神经元丢失（NeuN标记物）。SQXN处理通过抑制sAPPβ和BACE-1的表达降低可溶性Aβ42水平，而不调节全长淀粉样前体蛋白（FL APP）。SQXN可增加Aβ降解酶胰岛素降解酶（IDE）。此外，SQXN可降低APP/PS1小鼠脑中tau蛋白过度磷酸化水平，并防止p-GSK-3β过度激活。与APP/PS1转基因阴性小鼠相比，6.5月龄APP/PS1转基因（Tg）小鼠脑中IFN-γ、IL-1β、IL-2、IL-4、IL-5、IL-6、IL-12p70、KC/GRO和TNF-α无明显变化。然而，SQXN可抑制IL-2的表达。
这些结果表明，SQXN可改善APP/PS1小鼠的认知障碍。其可能机制包括抑制神经元丢失、可溶性Aβ沉积、tau蛋白过度磷酸化和炎症反应。
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