Tripchlorolide improves cognitive deficits by reducing amyloid β and upregulating synapse-related proteins in a transgenic model of Alzheimer's Disease
Tripchlorolide improves cognitive deficits by reducing amyloid β and upregulating synapse-related proteins in a transgenic model of Alzheimer's Disease
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DOI：
10.1111/jnc.13056
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发表时间：
2015-04-01
影响因子：
4.7
通讯作者：
Chen, Xiaochun
中科院分区：
文献类型：
--
作者：
Zeng, Yuqi;Zhang, Jian;Chen, Xiaochun
阿尔茨海默病（AD）的特征在于记忆的早期损伤和进行性神经变性。作为学习和记忆基础的突触可塑性过程的破坏部分地促成了这种病理生理学。雷公藤氯甙（T-4）是一种传统中草药雷公藤的提取物，已被证明在帕金森病的动物模型中具有神经保护作用，并可改善衰老加速小鼠P8的认知缺陷。在这项研究中，我们研究了T-4对共表达突变的淀粉样前体蛋白和早老素-1的5倍家族性AD（5XFAD）小鼠的认知能力下降和突触可塑性的影响。5月龄的5XFAD小鼠和野生型同窝小鼠每隔一天腹腔内注射5g/kg或25 g/kg的T-4，持续60天。T-4处理显著改善空间学习和记忆，减轻突触超微结构退化，上调突触相关蛋白的表达，包括突触素、突触后密度-95、N-甲基-D-天冬氨酸受体亚单位1、钙/钙调蛋白依赖性蛋白激酶II的磷酸化和环AMP-反应元件结合蛋白的磷酸化，并促进5XFAD小鼠中磷酸肌醇-3-激酶-Akt-哺乳动物雷帕霉素靶信号通路的活化。淀粉样蛋白（A）的积累可能有助于AD中突触功能障碍和记忆障碍。我们发现，T-4治疗显着减少脑A存款和降低脑匀浆中的A水平。这些影响与羧基末端淀粉样前体蛋白（APP）片段的裂解减少，可溶性APP的水平，以及-位点APP裂解酶1的蛋白质表达一致。综上所述，我们的研究结果确定T-4作为脑A水平的有效负调节剂，并表明它显着改善AD小鼠模型中的突触变性和认知缺陷。
Alzheimer's disease (AD) is characterized by early impairments in memory and progressive neurodegeneration. Disruption of synaptic plasticity processes that underlie learning and memory contribute partly to this pathophysiology. Tripchlorolide (T-4), an extract from a traditional Chinese herbal Tripterygium wilfordii Hook F, has been shown to be neuroprotective in animal models of Parkinson's disease and to improve cognitive deficits in senescence-accelerated mouse P8. In this study, we investigated the effect of T-4 on cognitive decline and synaptic plasticity in five times familial AD (5XFAD) mice co-expressing mutated amyloid precursor protein and presenilin-1. Five-month-old 5XFAD mice and wild type littermates were intraperitoneally injected with T-4, 5g/kg or 25g/kg, every other day for 60days. T-4 treatment significantly improved spatial learning and memory, alleviated synaptic ultrastructure degradation, up-regulated expression of synapse-related proteins, including synaptophysin, post-synaptic density-95, N-methyl-D-aspartate receptor subunit 1, phosphorylation of calcium/calmodulin dependent protein kinase II , and phosphorylation of cyclic AMP-response element binding protein, and promoted activation of the phophoinositide-3-kinase-Akt-mammalian target of rapamycin signaling pathway in 5XFAD mice. Accumulation of amyloid (A) may contribute to synapse dysfunction and memory impairment in AD. We found that T-4 treatment significantly reduced cerebral A deposits and lowered A levels in brain homogenates. These effects coincided with a reduction in cleavage of -carboxyl-terminal amyloid precursor protein (APP) fragment, levels of soluble APP, and protein expression of -site APP cleaving enzyme 1. Taken together, our findings identify T-4 as a potent negative regulator of brain A levels and show that it significantly ameliorates synaptic degeneration and cognitive deficits in a mouse model of AD.