Xie Ce, Miyasaka Tomohiro
College of Basic Medical Sciences, Dalian Medical UniversityDalian, China; Department of Neuropathology, Faculty of Life and Medical Sciences, Doshisha UniversityKyotanabe, Japan.
Department of Neuropathology, Faculty of Life and Medical Sciences, Doshisha University Kyotanabe, Japan.
Front Mol Neurosci. 2016 Dec 27;9:158. doi: 10.3389/fnmol.2016.00158. eCollection 2016.
Dementia includes several diseases characterized by acquired and irreversible brain dysfunctions that interfere with daily life. According to the etiology, dementia can be induced by poisoning or metabolic disorders, and other cases of dementia have a clear pathogenesis. However, half of neurodegenerative diseases have an unclear pathogenesis and etiology. Alzheimer's disease (AD), Lewy body dementia and frontal-temporal dementia are the three most common types of dementia. These neurodegenerative diseases are characterized by the appearance of the following specific protein inclusions: amyloid beta and tau in AD; α-synuclein in Lewy body dementia; and tau, TDP-43, or FUS in frontal-temporal dementia. Thus far, studies on the pathogenesis of dementia mainly focus aberrant inclusions formed by the aforementioned proteins. As a historically heavily studied protein tau is likely to be associated with the pathogenesis of several neurodegenerative diseases that cause dementia. The role of tau in neurodegeneration has been unknown for many years. However, both pathological and genetic analyses have helped tau become gradually recognized as an important factor in the pathogenesis of tauopathy. Currently, especially in the field of AD, tau is attracting more attention and is being considered a potential target for drug development. In this review article, previously discovered biochemical and pathological features of tau are highlighted, and current opinions regarding the neurotoxicity of tau are summarized. Additionally, we introduce key amino acid sequences responsible for tau neurotoxicity from our studies using transgenic . Finally, a new hypothesis regarding the roles of microtubule-associated protein 2 (MAP2) and tau in the pathogenesis of tauopathy is discussed.
痴呆症包括几种以获得性和不可逆性脑功能障碍为特征的疾病，这些脑功能障碍会干扰日常生活。根据病因，痴呆症可由中毒或代谢紊乱引起，其他类型的痴呆症则有明确的发病机制。然而，一半的神经退行性疾病的发病机制和病因尚不清楚。阿尔茨海默病（AD）、路易体痴呆和额颞叶痴呆是三种最常见的痴呆类型。这些神经退行性疾病的特征是出现以下特定的蛋白质包涵体：AD中的淀粉样β蛋白和tau蛋白；路易体痴呆中的α-突触核蛋白；以及额颞叶痴呆中的tau蛋白、TDP-43或FUS。迄今为止，关于痴呆症发病机制的研究主要集中在上述蛋白质形成的异常包涵体上。作为一种历史上受到大量研究的蛋白质，tau蛋白可能与几种导致痴呆症的神经退行性疾病的发病机制有关。多年来，tau蛋白在神经退行性变中的作用一直不为人知。然而，病理和基因分析都有助于tau蛋白逐渐被认为是tau蛋白病发病机制中的一个重要因素。目前，尤其是在AD领域，tau蛋白正受到越来越多的关注，并被视为药物开发的潜在靶点。在这篇综述文章中，我们重点介绍了先前发现的tau蛋白的生化和病理特征，并总结了目前关于tau蛋白神经毒性的观点。此外，我们通过转基因研究介绍了负责tau蛋白神经毒性的关键氨基酸序列。最后，我们讨论了关于微管相关蛋白2（MAP2）和tau蛋白在tau蛋白病发病机制中的作用的新假说。
