Long-term oral administration of hop flower extracts mitigates Alzheimer phenotypes in mice.
Long-term oral administration of hop flower extracts mitigates Alzheimer phenotypes in mice.
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DOI：
10.1371/journal.pone.0087185
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Kakizuka A
中科院分区：
文献类型：
--
作者：
Sasaoka N;Sakamoto M;Kanemori S;Kan M;Tsukano C;Takemoto Y;Kakizuka A
随着老年人口的不断增加，大多数发达国家的阿尔茨海默病（AD）发病率也在迅速增加。目前还没有有效的预防药物。在提出的AD的几种病理机制中，“淀粉样蛋白假说”已被最广泛接受，其中Aβ的积累或沉积被认为是初始事件。因此，预防Aβ产生将是治疗或预防AD的理想策略。Aβ是通过两种不同的酶β和γ-分泌酶对其前体蛋白APP（淀粉样前体蛋白）进行蛋白水解裂解而产生的。事实上，已经开发了针对任一种或两种酶的抑制剂，并测试了其临床功效。基于“淀粉样蛋白假说”，我们开发了一种基于β-淀粉酶的筛选方法来监测γ-分泌酶活性，筛选了1,600多种植物提取物，其中大部分长期用于中药，观察到啤酒花提取物显著抑制培养细胞中的Aβ产生。纯化了抑制活性的主要组分，并通过NMR确定其化学身份为Garcinielliptone HC。在体内，经口给予AD模型小鼠啤酒花提取物可减少顶叶、海马和脑动脉壁（淀粉样血管病）大脑皮质中的Aβ沉积。在Morris水迷宫测试中，每天饮用啤酒花提取物的AD模型小鼠在9和12个月大时表现出记忆障碍的显著减轻。此外，在旷场试验中，啤酒花提取物的口服给药也防止了AD小鼠在18个月时出现的情绪障碍。尽管终生食用啤酒花提取物，但在任何年龄都没有观察到有害的副作用。这些结果支持“淀粉样蛋白假说”，并表明啤酒花提取物是有效预防AD的有希望的候选药物。
Coincident with the expanding population of aged people, the incidence of Alzheimer disease (AD) is rapidly increasing in most advanced countries. At present, no effective prophylactics are available. Among several pathological mechanisms proposed for AD, the “amyloid hypothesis” has been most widely accepted, in which accumulation or deposition of Aβ is considered to be the initial event. Thus, prevention of Aβ production would be an ideal strategy for the treatment or prevention of AD. Aβ is produced via the proteolytic cleavage of its precursor protein, APP (amyloid precursor protein), by two different enzymes, β and γ-secretases. Indeed, inhibitors against either or both enzymes have been developed and tested for clinical efficacy. Based on the “amyloid hypothesis”, we developed a luciferase-based screening method to monitor γ-secretase activity, screened more than 1,600 plant extracts, most of which have long been used in Chinese medicine, and observed that Hop extracts significantly inhibit Aβ production in cultured cells. A major component of the inhibitory activity was purified, and its chemical identity was determined by NMR to be Garcinielliptone HC. In vivo, oral administration of Hop extracts to AD model mice decreased Aβ depositions in the cerebral cortex of the parietal lobe, hippocampus, and artery walls (amyloid angiopathy) in the brains. In a Morris water maze test, AD model mice that had daily consumed Hop extracts in their drinking water showed significant mitigation of memory impairment at ages of 9 and 12 months. Moreover, in the open field test oral administration of Hop extracts also prevented an emotional disturbance that appeared in the AD mice at 18 months. Despite lifelong consumption of Hop extracts, no deleterious side effects were observed at any age. These results support the “amyloid hypothesis”, and indicate that Hop extract is a promising candidate for an effective prophylactic for AD.
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DOI：
10.1126/science.1198668
发表时间：
2010-11-19
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Kelleher RJ 3rd;Shen J
通讯作者：
Shen J
影响因子：
64.8
作者：
JARRIAULT, S;BROU, C;ISRAEL, A
通讯作者：
ISRAEL, A
影响因子：
158.5
作者：
Howard, Robert;McShane, Rupert;Phillips, Patrick
通讯作者：
Phillips, Patrick
影响因子：
168.9
作者：
Ferri, CP;Prince, M;Scazufca, M
通讯作者：
Scazufca, M
影响因子：
64.8
作者：
Jonsson, Thorlakur;Atwal, Jasvinder K.;Stefansson, Kari
通讯作者：
Stefansson, Kari