我校大坪医院王延江教授团队在Acta Neuropathologica上发表研究成果
发布人:wuph 发布时间:1/15/2019 10:40:40 AM  浏览次数:1933次
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Tau蛋白的外周清除机制及其在tau蛋白病中的治疗潜能研究

王俊,刘雨辉,王延江

Tau蛋白是一种细胞内微管相关蛋白,其与微管蛋白结合以维持微管稳定性。病理状态下,tau蛋白过度磷酸化并聚集形成神经原纤维缠结(Neurofibrillary tangle, NFT),而NFT和淀粉样斑块是阿尔茨海默病的两大病理特征。此外,tau病理还见于进行性核上性麻痹、皮质基底节变性、Pick病、额颞叶痴呆、慢性损伤性脑病等,这一类以tau蛋白的异常磷酸化和沉积为特征的神经退行性疾病统称为tau蛋白病(Tauopathies)。Tau病理与神经元功能障碍、突触丢失和认知下降有关,可引起严重的认知、运动、社会功能障碍等,给家庭和社会都带来了严重的精神及经济负担。然而,tau蛋白病的发病机制尚未完全阐明,当前临床药物仅为对症治疗,不能阻止病情发展。因此,进一步揭示tau蛋白病的发病机制,建立有效的治疗方法,是当前面临的重要任务。

目前研究认为,病理性tau蛋白可被分泌到细胞外,并以朊蛋白样形式进行传播,从而实现tau病理从一个神经元到另一个神经元,最后从一个脑区到另一个脑区的传播。清除细胞外的病理性tau蛋白,切断该传播途径,或可成为预防tau病发展的有效手段。近期用抗tau寡聚体抗体进行被动免疫的研究发现,脑内病理性tau蛋白可经外周清除(peripheral sink)机制被清除,提示增强tau蛋白的外周清除或可成为tau蛋白病的一种治疗策略。

本研究中,研究人员首先探讨了外周系统是否具有tau蛋白的生理性清除功能。通过将放射性核素131I标记的tau蛋白(131I-tau)注入野生型小鼠的小脑延髓池,在15min、30min、1h、4h及8h后发现其放射性主要在血液、肾脏、肝脏被检测到,且随时间延长而下降,说明脑内tau蛋白可以流向外周,其在外周的主要清除部位包括血液、肾脏及肝脏等;然后通过检测人体不同部位(主动脉及下腔静脉)血液内tau蛋白水平发现,动脉血(经外周脏器代谢前)中tau蛋白水平显著高于下腔静脉(经外周脏器代谢后),进一步说明人体外周系统具有tau蛋白的生理性清除功能。其次,研究人员探讨了加强外周tau的清除是否可加速脑内tau蛋白的外流。通过给tau转基因鼠进行腹膜透析,并动态监测小鼠血液及脑组织间液(ISF)中的tau蛋白水平,发现腹膜透析在清除血液tau蛋白的同时也可以有效清除脑内tau蛋白,提示降低血液tau蛋白水平可促进脑内tau的外流;然后通过将两个野生型小鼠并联,使其循环血液互通,然后给其中一只小鼠的小脑延髓池内注射131I-tau,并检测不同时间点的脑组织及外周各脏器的放射性,发现并联注射侧小鼠脑内tau蛋白下降速度比未并联野生型小鼠快,进一步说明增加外周tau的清除可加速脑内tau的外流及清除。最后,研究者通过将tau转基因鼠与野生型小鼠并联,从而给转基因鼠提供一套额外的外周脏器,3个月后发现并联转基因鼠脑内tau病理较对照组转基因鼠显著降低,且神经变性及炎症等情况亦有所改善,提示慢性增加tau的外周清除可改善脑内tau病理及其介导的神经变性。

该研究首次证明外周系统具有生理性清除tau蛋白的功能,并揭示加强外周tau蛋白的清除或可成为tau蛋白病的潜在治疗手段,也为其他神经变性疾病从系统角度阐明发病机制及寻找治疗策略提供提供新思路。上述研究结果于2018年10月以论著形式发表在神经科学领域杂志Acta Neuropathologica (IF=15.872)。

Physiological clearance of tau in the periphery and its therapeutic potential for tauopathies

Running title: Peripheral tau clearance for tauopathies

 

Jun Wang1, Wang-Sheng Jin1, Xian-Le Bu1, Fan Zeng1, Zhi-Lin Huang3, Wei-Wei Li1, Lin-Lin Shen1, Zhen-Qian Zhuang1, Yuqiang Fang4, Bin-Lu Sun1, Jie Zhu1, Xiu-Qing Yao1, Gui-Hua Zeng1, Zhi-Fang Dong3, Jin-Tai Yu5, Zhian Hu6, Weihong Song7, Hua-Dong Zhou1, Jian-Xin Jiang2, Yu-Hui Liu1,*, Yan-Jiang Wang1,2,8,*

 

1 Department of Neurology, Daping Hospital, Third Military Medical University, Chongqing, China.

2 State Key Laboratory of Trauma, Burn and Combined Injury, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, China.

3 Ministry of Education Key Laboratory of Child Development and Disorders and Chongqing Key Laboratory of Translational Medical Research in Cognitive Development and Learning and Memory Disorders, Children’s Hospital of Chongqing Medical University, Chongqing, China.

4 Department of Cardiology, Daping Hospital, Third Military Medical University, Chongqing, China.

5 Department of Neurology, Qingdao Municipal Hospital, School of Medicine, Qingdao University, Qingdao, China.

6 Department of Physiology, Collaborative Innovation Center for Brain Science, Third Military Medical University, Chongqing, China

7 Townsend Family Laboratories, Department of Psychiatry, Brain Research Center, The University of British Columbia, Vancouver, BC V6T 1Z3, Canada.

8 Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, China.

Abstract

       Accumulation of pathological tau is the hallmark of Alzheimer’s disease and other tauopathies and is closely correlated with cognitive decline. Clearance of pathological tau from the brain is a major therapeutic strategy for tauopathies. The physiological capacity of the periphery to clear brain-derived tau and its therapeutic potential remain largely unknown. Here, we found that cisterna magna injected 131I-labelled synthetic tau dynamically effluxed from the brain and was mainly cleared from the kidney, blood and liver in mice; we also found that plasma tau levels in inferior vena cava were lower than those in femoral artery in humans. These findings suggest that tau proteins can efflux out of the brain and be cleared in the periphery under physiological conditions. Next, we showed that lowering blood tau levels via peritoneal dialysis could reduce interstitial fluid (ISF) tau levels in the brain, and tau levels in the blood and ISF were dynamically correlated; Furthermore, tau efflux from the brain was accelerated after addition of another set of peripheral system in a parabiosis model. Finally, we established parabiosis mouse models using tau transgenic mice and their wild-type littermates and found that brain tau levels and related pathologies in parabiotic transgenic mice were significantly reduced after parabiosis, suggesting that chronic enhancement of peripheral tau clearance alleviates pathological tau accumulation and neurodegeneration in the brain. Our study provides the first evidence of physiological clearance of brain-derived pathological tau in the periphery, suggesting that enhancing peripheral tau clearance is a potential therapeutic strategy for tauopathies.

Keywords: Tauopathy; Parabiosis; Peritoneal dialysis; Tau; Clearance; Periphery

王俊,陆军军医大学2015级博士研究生,神经病学专业,导师为陆军特色医学中心神经内科王延江教授。主要从事阿尔茨海默病及tau蛋白病的防治研究。主持国家自然科学基金青年项目1项。以第一作者(含共同)在《Nature Reviews Neurology》、《Acta Neuropathologica》等杂志发表SCI论文11篇,影响因子10以上文章2篇,累计影响因子79.2Email address: qywangjun@163.com

 

刘雨辉,神经病学博士,陆军特色医学中心神经内科主治医师,讲师,现为中国阿尔茨海默病防治学会会员,Brain杂志中文版青年编委。入选陆军军医大学苗圃人才库。曾获得2016年国际阿尔茨海默病年会旅行奖。近年来开展阿尔茨海默病的基础和临床研究,主持国家自然科学基金1项,重庆市自然基金1项。以第一作者(含共同)或通讯作者(含共同)在《Nature Reviews Neurology》、《PNAS》、《Acta Neuropathologica》等杂志发表SCI论文12篇,影响因子10以上论文3篇,累计影响因子98.9,他引277次。Email address: liuyuhui07-8909@163.com

王延江,男,医学博士(中国),PhD(澳大利亚),陆军特色医学中心神经内科主任、主任医师、博士生导师,国家杰青,长江学者特聘教授,国家“万人计划”领军人才。临床和科研方向为老年痴呆和脑血管病。以第一或通讯作者发表SCI论文50余篇。参与获得国家科技进步二等奖1项,省部级一等奖3项。Email address: yanjiang_wang@tmmu.edu.cn

 


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