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:2017/9/29 11:04:05  浏览次数:525次
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腹膜透析清除脑内和改善阿尔茨海默病相关病理的作用和机制

金旺盛 王延江

阿尔茨海默病(Alzheimer’s disease, AD)是目前老年人中最主要的痴呆类型,是一种以进行性的记忆能力下降和认知功能障碍为特征的神经退行性疾病。AD病因复杂,迄今为止,其发病机制尚未阐述清楚。

传统观点认为,AD 是大脑自身的疾病。脑内 β-淀粉样肽(Amyloid-beta, Aβ)沉积形成的Aβ斑块(Aβ plaque)是AD最主要的病理特征。目前占主流地位的Aβ 级联假说认为,AD的主要发生机制是脑内Aβ的过度产生或清除障碍导致Aβ 在脑内过度沉积,诱发神经炎症、Tau蛋白过度磷酸化、脑内氧化应激以及神经变性死亡,最终导致痴呆。目前尚无有效预防或延缓AD进展的药物和方法。近年来开展的一系列针对Aβ产生和清除的临床试验都未能取得预期疗效。总结临床试验失败的重要原因是治疗同时伴随的严重副作用。在免疫治疗临床试验中,抗体或药物进入脑内,在与脑内Aβ直接作用同时,会导致脑水肿、微出血、无菌性脑膜脑炎以及神经元兴奋性毒性等副作用。同时,大脑功能的正常运行需要一个高度稳定的内环境,外源性药物通过血脑屏障进入脑内,可改变大脑内环境稳态,从而存在诱发不良反应的潜在风险。避免药物进入脑内,通过清除血液Aβ来促进脑内Aβ外流和清除,可能是更为安全的有效Aβ清除策略。我们过去研究发现,机体外周脏器组织在清除脑内Aβ方面具有重要作用,提示增强Aβ外周清除能力有望成为一种安全有效的AD治疗策略,值得探讨。

腹膜透析( Peritoneal Dialysis, PD)常被用于清除血液以及脑内的有毒物质,有望成为新的Aβ外周清除措施。为此,本研究通过临床实验和动物实验探讨了腹膜透析清除血液Aβ,防治AD的有效性和可行性。这些研究的完成,有助于从系统性角度来理解AD发生机制,寻找有效防治措施。

本论文中,研究人员首先探讨了腹膜透析对人体血液中Aβ水平的影响。通过比较初次接受腹膜透析的慢性肾病患者在透析前后血液中Aβ水平发现腹膜透析可以有效清除人体血液中的Aβ。为进一步探究腹膜透析对于中枢Aβ的作用,研究人员选用了APP/PS1小鼠,即携带AD相关基因APP与PS1的转基因小鼠模型。通过与临床术式相近的手术方法建立了小鼠腹膜透析模型。同时,应用微透析技术在接受腹膜透析的APP/PS1小鼠脑内进行动态微量生化取样,获得可反映脑内可溶性Aβ水平的样本。按时间节点对比APP/PS1小鼠腹膜透析过程中血液Aβ水平与脑内微透析样本Aβ水平,发现腹膜透析在清除血液中的Aβ的同时也可以有效清除脑内可溶性Aβ。这说明外周系统与大脑内Aβ的交流并不存在障碍,为本研究奠定了工作基础。那么,腹膜透析是否具有AD防治前景呢?为此,研究人员进行了为期一个月的长期腹膜透析小鼠实验。研究发现腹膜透析可以显著清除APP/PS1小鼠脑内的Aβ沉积,缓解脑内炎症反应,恢复脑内微环境的稳定,并改善脑内AD相关病理改变。

上述研究结果于2017年5月以论著形式发表在神经科学权威杂志《Acta Neuropathologica》 (IF=12.213)。该研究是课题组外周清除学术思想的发展,再次为外周途经防治AD提供了证据,提示了改善大脑微环境对AD防治的重要意义,也为其他神经退行性疾病的防治提供了新思路。

 全文浏览:http://xueshu.baidu.com/s?wd=paperuri%3A%28b938ec5ff2e4712dcccb057177266467%29&filter=sc_long_sign&tn=SE_xueshusource_2kduw22v&sc_vurl=http%3A%2F%2Flink.springer.com%2F10.1007%2Fs00401-017-1721-y&ie=utf-8&sc_us=12441022619988481990

 

Peritoneal dialysis reduces amyloidbeta plasma levels in humansand attenuates Alzheimerassociated phenotypes in an APP/PS1mouse model

 

Wang-Sheng Jin1, Lin-Lin Shen1, Xian-Le Bu1, Wei-Wei Zhang2, Si-Han Chen1, Zhi-Lin Huang3, Jia-Xiang Xiong4, Chang-Yue Gao1, Zhifang Dong3, Ya-Ni He2, Zhi-An Hu4, Hua-Dong Zhou1, Weihong Song5, Xin-Fu Zhou6, Yi-Zheng Wang7,Yan-Jiang Wang1,*

1 Department of Neurology and Centre for Clinical Neuroscience, Daping Hospital, Third Military Medical University, Chongqing, China.

2 Department of Nephrology, 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 Physiology, Third Military Medical University, Chongqing, China.

5 Townsend Family Laboratories, Department of Psychiatry, Center for Brain Health, The University of British Columbia, Vancouver, BC V6T1Z3, Canada.

6 School of Pharmacy and Medical Sciences and Sansom Institute, University of South Australia, Adelaide, Australia.

7 Laboratory of Neural Signal Transduction, Institute of Neuroscience, Chinese Academy of Science, Shanghai, China

Abstract

Clearance of amyloid-beta (Aβ) from the brain is an important therapeutic strategy for Alzheimer’s disease (AD). Current studies mainly focus on the central approach of Aβ clearance by introducing therapeutic agents into the brain. In a previous study, we found that peripheral tissues and organs play important roles in clearing brain-derived Aβ, suggesting that the peripheral approach of removing Aβ from the blood may also be effective for AD therapy. Here, we investigated whether peritoneal dialysis, a clinically available therapeutic method for chronic kidney disease (CKD), reduces brain Aβ burden and attenuates AD-type pathologies and cognitive impairments. Thirty patients with newly diagnosed CKD were enrolled. The plasma Aβ concentrations of the patients were measured before and after peritoneal dialysis. APP/PS1 mice were subjected to peritoneal dialysis once a day for one month from 6 months of age (prevention study) or 9 months of age (treatment study). The Aβ in the interstitial fluid (ISF) was collected using microdialysis. Behavioural performance, long-term potentiation (LTP), Aβ burden and other AD-type pathologies were measured after one month of peritoneal dialysis. Peritoneal dialysis significantly reduced plasma Aβ levels in both CKD patients and APP/PS1 mice. Aβ levels in the brain ISF of APP/PS1 mice immediately decreased after reduction of Aβ in the blood during peritoneal dialysis. In both prevention and treatment studies, peritoneal dialysis substantially reduced Aβ deposition, attenuated other AD-type pathologies, including Tau hyperphosphorylation, glial activation, neuroinflammation, neuronal loss, and synaptic dysfunction, and rescued the behavioural deficits of APP/PS1 mice. Importantly, the Aβ phagocytosis function of microglia was enhanced in APP/PS1 mice after peritoneal dialysis. Our study suggests that peritoneal dialysis is a promising therapeutic method for AD, and Aβ clearance using a peripheral approach could be a desirable therapeutic strategy for AD.

 

Key words: Alzheimer’s disease; Amyloid-beta; Peritoneal dialysis; Neurodegeneration; Peripheral clearance


 

 

 

金旺盛,2009年考入第三军医大学临床医学八年制本硕博连读专业。2014年至今,第三军医大学大坪医院神经内科博士研究生,导师为王延江教授。主要从事阿尔茨海默病外周途径防治研究。目前以第一或共同第一作者发表SCI论文4篇,单篇最高影响因子12.2Email address:skjws123@163.com

 

 

王延江,男,医学博士(中国),PhD(澳大利亚),第三军医大学大坪医院神经内科主任、主任医师、博士生导师,国家杰青,中国老年医学会认知障碍分会副会长、中国药理学会抗衰老与老年痴呆专业委员会副主任委员、亚洲血管性认知障碍学会理事等职务。以第一或通讯作者在Molecular PsychiatryActaNeuropathologicaPNASNature Review Neurology等国外杂志发表论文40余篇,影响因子10以上论文6篇,单篇最高影响因子20.2Email address: yanjiang_wang@tmmu.edu.cn


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