Berberine ameliorates β-amyloid pathology, gliosis, and cognitive impairment in an Alzheimer's disease transgenic mouse model
Berberine ameliorates β-amyloid pathology, gliosis, and cognitive impairment in an Alzheimer's disease transgenic mouse model
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DOI：
10.1016/j.neurobiolaging.2012.02.016
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发表时间：
2012-12-01
影响因子：
4.2
通讯作者：
Li, Min
中科院分区：
文献类型：
--
作者：
Durairajan, Siva Sundara Kumar;Liu, Liang-Feng;Li, Min
淀粉样前体蛋白（APP）异常加工产生的β-淀粉样（Aβ）肽的积累是阿尔茨海默病（AD）大脑的常见病理标志。在这项研究中，我们评估了从中药黄连中提取的小檗碱 (BBR) 对 TgCRND8 小鼠（一种成熟的 AD 转基因小鼠模型）神经病理学和认知障碍的治疗效果。两个月大的 TgCRND8 小鼠通过口服管饲法接受低剂量（每天 25 毫克/千克）或高剂量（每天 100 毫克/千克）BBR，直到 6 个月大。与载体对照治疗相比，BBR 治疗显着改善了学习缺陷、长期空间记忆保留以及斑块负荷。此外，酶联免疫吸附测定 (ELISA) 测量表明，BBR 处理的小鼠脑匀浆中可溶性和不溶性 β-淀粉样蛋白的水平显着降低。糖原合成酶激酶 (GSK)3 是参与 APP 和 tau 磷酸化的主要激酶，BBR 处理显着抑制该激酶。我们还发现，在稳定表达人瑞典突变体 APP695 (N2a-SwedAPP) 的 N2a 小鼠神经母细胞瘤细胞中，BBR 通过 Akt/糖原合酶激酶 3 信号通路显着降低 APP C 端片段的水平以及 APP 和 tau 的过度磷酸化。我们的结果表明，BBR 通过调节 APP 处理为 TgCRND8 小鼠提供神经保护作用，并且有必要进一步研究 BBR 在 AD 治疗中的应用。 (C) 2012 Elsevier Inc. 保留所有权利。
The accumulation of beta-amyloid(A beta) peptide derived from abnormal processing of amyloid precursor protein (APP) is a common pathological hallmark of Alzheimer's disease (AD) brains. In this study, we evaluated the therapeutic effect of berberine (BBR) extracted from Coptis chinensis Franch, a Chinese medicinal herb, on the neuropathology and cognitive impairment in TgCRND8 mice, a well established transgenic mouse model of AD. Two-month-old TgCRND8 mice received a low (25 mg/kg per day) or a high dose of BBR (100 mg/kg per day) by oral gavage until 6 months old. BBR treatment significantly ameliorated learning deficits, long-term spatial memory retention, as well as plaque load compared with vehicle control treatment. In addition, enzyme-linked immunosorbent assay (ELISA) measurement showed that there was a profound reduction in levels of detergent-soluble and -insoluble beta-amyloid in brain homogenates of BBR-treated mice. Glycogen synthase kinase (GSK)3, a major kinase involved in APP and tau phosphorylation, was significantly inhibited by BBR treatment. We also found that BBR significantly decreased the levels of C-terminal fragments of APP and the hyperphosphorylation of APP and tau via the Akt/glycogen synthase kinase 3 signaling pathway in N2a mouse neuroblastoma cells stably expressing human Swedish mutant APP695 (N2a-SwedAPP). Our results suggest that BBR provides neuroprotective effects in TgCRND8 mice through regulating APP processing and that further investigation of the BBR for therapeutic use in treating AD is warranted. (C) 2012 Elsevier Inc. All rights reserved.