Zeng Yuqi, Zhang Jian, Zhu Yuangui, Zhang Jing, Shen Hui, Lu Jianping, Pan Xiaodong, Lin Nan, Dai Xiaoman, Zhou Meng, Chen Xiaochun
Department of Neurology and Geriatrics, Fujian Institute of Geriatrics, Fujian Medical University Union Hospital, Fuzhou, China; Key Laboratory of Brain Aging and Neurodegenerative Disease, Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, China.
J Neurochem. 2015 Apr;133(1):38-52. doi: 10.1111/jnc.13056. Epub 2015 Mar 8.
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 (T4 ), 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 T4 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 T4 , 5 μg/kg or 25 μg/kg, every other day for 60 days. T4 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 α, 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 β (Aβ) may contribute to synapse dysfunction and memory impairment in AD. We found that T4 treatment significantly reduced cerebral Aβ deposits and lowered Aβ levels in brain homogenates. These effects coincided with a reduction in cleavage of β-carboxyl-terminal amyloid precursor protein (APP) fragment, levels of soluble APPβ, and protein expression of β-site APP cleaving enzyme 1. Taken together, our findings identify T4 as a potent negative regulator of brain Aβ levels and show that it significantly ameliorates synaptic degeneration and cognitive deficits in a mouse model of AD.
阿尔茨海默病（AD）的特征是早期记忆受损和进行性神经退行性变。作为学习和记忆基础的突触可塑性过程的破坏在一定程度上导致了这种病理生理过程。雷公藤甲素（T4）是从传统中药雷公藤中提取的成分，已显示在帕金森病动物模型中具有神经保护作用，并能改善快速老化小鼠P8的认知缺陷。在本研究中，我们研究了T4对共表达突变淀粉样前体蛋白和早老素-1的五倍体家族性AD（5XFAD）小鼠认知衰退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注射5μg/kg或25μg/kg的T4，持续60天。T4治疗显著改善了空间学习和记忆，减轻了突触超微结构退化，上调了突触相关蛋白的表达，包括突触素、突触后致密蛋白95、N-甲基-D-天冬氨酸受体亚基1、钙/钙调蛋白依赖性蛋白激酶IIα的磷酸化以及环磷酸腺苷反应元件结合蛋白的磷酸化，并促进了5XFAD小鼠中磷酸肌醇-3-激酶-蛋白激酶B-雷帕霉素靶蛋白信号通路的激活。β淀粉样蛋白（Aβ）的积累可能导致AD中的突触功能障碍和记忆损害。我们发现T4治疗显著减少了脑内Aβ沉积，并降低了脑匀浆中的Aβ水平。这些作用与β-羧基末端淀粉样前体蛋白（APP）片段的裂解减少、可溶性APPβ水平以及β-位点APP裂解酶1的蛋白表达降低相一致。综上所述，我们的研究结果确定T4是脑Aβ水平的有效负调节因子，并表明它能显著改善AD小鼠模型中的突触退化和认知缺陷。
