Long-term treatment with Ginkgo biloba extract EGb 761 improves symptoms and pathology in a transgenic mouse model of Alzheimer's disease
Long-term treatment with Ginkgo biloba extract EGb 761 improves symptoms and pathology in a transgenic mouse model of Alzheimer's disease
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DOI：
10.1016/j.bbi.2015.01.011
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发表时间：
2015-05-01
影响因子：
15.1
通讯作者：
Liu, Yang
中科院分区：
文献类型：
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作者：
Liu, Xu;Hao, Wenlin;Liu, Yang
阿尔茨海默病（Alzheimer's disease，AD）是一种以淀粉样蛋白13肽（amyloid 13 peptide，A β）的细胞外沉积和小胶质细胞主导的神经炎症为特征的神经退行性疾病。目前AD的治疗选择有限。在这项研究中，我们研究了银杏叶提取物EGb 761给药TgCRND 8 AD小鼠时的抑制作用和潜在的分子机制，TgCRND 8 AD小鼠在神经元中特异性过表达人阿尔茨海默氏淀粉样前体蛋白（APP）。我们给APP转基因小鼠EGb 761作为膳食补充剂2或5个月。小鼠中EGb 761组分的血浆浓度与以推荐剂量（每日240 mg）服用EGb 761的人体中的浓度范围相同。通过巴恩斯迷宫试验测定，EGb 761治疗5个月显著改善了小鼠的认知功能。EGb 761还减轻了突触结构蛋白（如PSD-95、Munc 18 -1和SNAP 25）的丢失。用EGb 761治疗5个月可抑制脑中小胶质细胞的炎症活化。EGb 761治疗2个月的效果较弱，无统计学显著性。此外，EGb 761激活小胶质细胞中的自噬。用EGb 761处理降低了A β诱导的小胶质细胞分泌TNF-α和IL-1 β以及激活caspase-1，这两者都被自噬抑制所消除。EGb 761处理还降低了与小胶质细胞中LC 3阳性自噬体或自溶酶体共定位的NLRP 3蛋白的浓度。此外，EGb 761长期治疗可通过抑制β-分泌酶活性和A β聚集来减少脑A β病理。因此，长期使用G.银杏叶提取物EGb 761是一种临床上可用且耐受性良好的草药，通过β-淀粉样蛋白和AB导向机制改善AD病理学。(C)2015 Elsevier Inc. All rights reserved.
Alzheimer's disease (AD) is a neurodegenerative disease characterized by extracellular deposits of amyloid 13 peptide (A beta) and microglia-dominated neuroinflammation. The therapeutic options for AD are currently limited. In this study, we investigated the antiinflammatory effects and the underlying molecular mechanisms of Ginkgo biloba extract EGb 761 when administered to TgCRND8 AD mice, which overexpress human Alzheimer's amyloid precursor protein (APP) specifically in neurons. We gave APP-transgenic mice EGb 761 as a dietary supplement for 2 or 5 months. Plasma concentrations of EGb 761 components in mice were in the same range as such concentrations in humans taking EGb 761 at the recommended dose (240 mg daily). Treatment with EGb 761 for 5 months significantly improved the cognitive function of the mice as measured by the Barnes Maze test It also attenuated the loss of synaptic structure proteins, such as PSD-95, Munc18-1, and SNAP25. Treatment with EGb 761 for 5 months inhibited microglial inflammatory activation in the brain. The effects of treatment with EGb 761 for 2 months were weak and not statistically significant. Moreover, EGb 761 activated autophagy in microglia. Treatment with EGb 761 decreased A beta-induced microglial secretion of TNF-alpha and IL-1 beta and activation of caspase-1, both of which were abolished by the inhibition of autophagy. Treatment with EGb 761 also reduced the concentrations of NLRP3 protein that colocalized with LC3-positive autophagosomes or autolysosomes in microglia. Additionally, long-term treatment with EGb 761 may reduce cerebral A beta pathology by inhibiting beta-secretase activity and A beta aggregation. Therefore, long-term treatment with G. biloba extract EGb 761, a clinically available and well-tolerated herbal medication, ameliorates AD pathology by antiinflammatory and AB-directed mechanisms. (C) 2015 Elsevier Inc. All rights reserved.