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tau蛋白与哺乳动物雷帕霉素靶蛋白:阿尔茨海默病发展过程中多种疾病的热点因素

Tau and mTOR: The Hotspots for Multifarious Diseases in Alzheimer's Development.

作者信息

Mueed Zeba, Tandon Pallavi, Maurya Sanjeev Kumar, Deval Ravi, Kamal Mohammad A, Poddar Nitesh Kumar

机构信息

Department of Biotechnology, Invertis University, Bareilly, India.

King Fahad Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia.

出版信息

Front Neurosci. 2019 Jan 10;12:1017. doi: 10.3389/fnins.2018.01017. eCollection 2018.

Abstract

The hyperphosphorylation of tau protein and the overexpression of mTOR are considered to be the driving force behind Aβ plaques and Neurofibrillay Tangles (NFT's), hallmarks of Alzheimer's disease (AD). It is now evident that miscellaneous diseases such as Diabetes, Autoimmune diseases, Cancer, etc. are correlated with AD. Therefore, we reviewed the literature on the causes of AD and investigated the association of tau and mTOR with other diseases. We have discussed the role of insulin deficiency in diabetes, activated microglial cells, and dysfunction of blood-brain barrier (BBB) in Autoimmune diseases, Presenilin 1 in skin cancer, increased reactive species in mitochondrial dysfunction and deregulated Cyclins/CDKs in promoting AD pathogenesis. We have also discussed the possible therapeutics for AD such as GSK3 inactivation therapy, Rechaperoning therapy, Immunotherapy, Hormonal therapy, Metal chelators, Cell cycle therapy, γ-secretase modulators, and Cholinesterase and BACE 1-inhibitors which are thought to serve a major role in combating pathological changes coupled with AD. Recent research about the relationship between mTOR and aging and hepatic Aβ degradation offers possible targets to effectively target AD. Future prospects of AD aims at developing novel drugs and modulators that can potentially improve cell to cell signaling, prevent Aβ plaques formation, promote better release of neurotransmitters and prevent hyperphosphorylation of tau.

摘要

tau蛋白的过度磷酸化和mTOR的过表达被认为是β淀粉样蛋白斑和神经纤维缠结(NFTs)背后的驱动力,而β淀粉样蛋白斑和神经纤维缠结是阿尔茨海默病(AD)的标志。现在很明显,诸如糖尿病、自身免疫性疾病、癌症等各种疾病都与AD相关。因此,我们回顾了关于AD病因的文献,并研究了tau和mTOR与其他疾病的关联。我们讨论了糖尿病中胰岛素缺乏的作用、自身免疫性疾病中活化的小胶质细胞和血脑屏障(BBB)功能障碍、皮肤癌中早老素1、线粒体功能障碍中反应性物质增加以及细胞周期蛋白/细胞周期蛋白依赖性激酶失调在促进AD发病机制中的作用。我们还讨论了AD的可能治疗方法,如糖原合酶激酶3(GSK3)失活疗法、再伴侣疗法、免疫疗法、激素疗法、金属螯合剂、细胞周期疗法、γ-分泌酶调节剂以及胆碱酯酶和β-分泌酶1(BACE 1)抑制剂,这些被认为在对抗AD相关的病理变化中起主要作用。最近关于mTOR与衰老以及肝脏β淀粉样蛋白降解之间关系的研究提供了有效靶向AD的可能靶点。AD的未来前景旨在开发能够潜在改善细胞间信号传导、预防β淀粉样蛋白斑形成、促进神经递质更好释放并防止tau过度磷酸化的新型药物和调节剂。

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