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神经药理学报››2011,Vol. 1››Issue (5): 34-39.

Tau蛋白异常导致阿尔茨海默病等神经退行性Tau蛋白病的机制与研究进展

李礼轩¹，李晓辉²

1．重庆医科大学临床医学系，重庆，400016，中国
2．第三军医大学药学院药物研究所，重庆，400038，中国

出版日期:2011-10-26发布日期:2013-03-24
通讯作者:李晓辉，男，教授，博士，博士生导师；研究方向：抗炎免疫与神经药理学；Tel：+86-023-68752318，Fax：+86-023-68753397，E-mail:lpsh008@yahoo.com.cn
作者简介:李礼轩，男，重庆医科大学2007级临床医学系本科生；E-mail: 1191123502 @qq.com
基金资助:

国家自然科学基金（No.30973523）

The Mechanisms and Research Progress of Tau Abnormality Leading to AD Related Neurodegenerative Taupathies

LI Li-xuan¹, LI Xiao-hui²

1. Faculty of Clinical Medicine, Chongqing Medical University, chongqing, 400016, China
2. Institute of Materia Medica, college of Pharmacy, the Third Military Medical University, Chongqing, 400038, China

Online:2011-10-26Published:2013-03-24
Contact:李晓辉，男，教授，博士，博士生导师；研究方向：抗炎免疫与神经药理学；Tel：+86-023-68752318，Fax：+86-023-68753397，E-mail:lpsh008@yahoo.com.cn
About author:李礼轩，男，重庆医科大学2007级临床医学系本科生；E-mail: 1191123502 @qq.com
Supported by:

国家自然科学基金（No.30973523）

摘要/Abstract

摘要：Tau蛋白是神经细胞特有的微管相关蛋白，其基本功能是促进微管蛋白组装成微管，维持正常神经轴突运输及微管稳定性。既往基于尸检发现脑部神经纤维缠结（neurofibrillary tangles，NFTs) 与神经元死亡、细胞形态异常及凋亡之间呈良好的平行关系，因而NFTs被认为是引起神经退行性Tau蛋白病的重要原因，并认为与Tau蛋白的过磷酸化有关；但新近发现单纯Tau蛋白磷酸化并不足以形成NFTs，还必须有其他诸如糖基化、脯氨酸异构化、泛素化等翻译后修饰机制的协同，其他如Tau蛋白基因突变、自噬的抑制等也与NFTs形成有关。尤其是最近采用转基因活体动物和多光子影像技术的研究显示，NFTs可能只是疾病晚期的临床表现，而可溶性的Tau蛋白才是启动下游病理反应的关键因素。更为引人注目的是，抑制Tau蛋白还可以阻止Aβ引起的神经细胞凋亡、减轻记忆损害，换言之即Aβ的毒性是Tau蛋白依赖性的。随着近期对Tau蛋白异常介导神经退行性Tau蛋白病及其机制的新认识以及以Aβ为靶点的药物研发宣告失败，人们愈来愈重视以Tau 为靶点的药物开发。

关键词:Tau蛋白,A&,beta,神经退行性变,阿尔茨海默病,药物靶点

Abstract:Tau, as a neuronally specific microtubule associated protein, plays a key role in promoting tubulin associated microtubule assembly, sustaining normal neuron axonal transport and stabilizing microtubule structure. Previous studies in autopsy revealed a tangible parallel relationship of brain neurofibrillary tangles (NFTs) to neurodegeneration, cell dysmorphology and apoptosis, thus leading to the consensus of NFTs being the major pathogenic factor in neurodegenerative taupathies, which are related to tau protein hyperphosphorylation. However, recent discoveries showed that Tau phosphorylation alone is insufficient for the formation of NFTs; other post-translational modifications such as glycosylation, proline isomerization, ubiquitination, as well as tau gene mutation and autophagy inhibition, are also required. In particular, recent researches using transgenic animals and multiphoton imaging technology indicated that NFTs seem to be just one clinical manifestation at the advanced stage of this disease, whereas soluble Tau protein plays an important role in initiating downstream pathological processes. Remarkably, suppression of Tau prohibited Aβ induced neuronal apoptosis and reduced memory impairment, suggesting that Aβ toxicity is Tau protein dependent. Along with the recent new light shed on the Tau abnormality induced neurodegenerative taupathies and its mechanism, Aβ as a drug target proved to be a failure in the field of drug discovery. As a result increasing attention has been given to tau targeted drug development.

Key words:tau protein,A&,beta,neurodegeneration,Alzheimer 's disease,therapeutic target

中图分类号:

R964

李礼轩, 李晓辉. Tau蛋白异常导致阿尔茨海默病等神经退行性Tau蛋白病的机制与研究进展[J]. 神经药理学报, 2011, 1(5): 34-39.

LI Li-xuan, LI Xiao-hui. The Mechanisms and Research Progress of Tau Abnormality Leading to AD Related Neurodegenerative Taupathies[J]. ACTA NEUROPHARMACOLOGICA, 2011, 1(5): 34-39.

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Tau蛋白异常导致阿尔茨海默病等神经退行性Tau蛋白病的机制与研究进展

The Mechanisms and Research Progress of Tau Abnormality Leading to AD Related Neurodegenerative Taupathies

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