Lucke-Wold Brandon, Seidel Kay, Udo Rub, Omalu Bennet, Ornstein Mark, Nolan Richard, Rosen Charles, Ross Joel
Department of Neurosurgery, West Virginia University School of Medicine, Morgantown, WV.
Dr. Senckenberg Chronomedical Institute, J. W. Goethe University, Frankfurt am Main, Germany.
J Neurol Neurosurg. 2017;4(2). Epub 2017 Dec 7.
Progressive neurodegenerative diseases plague millions of individuals both in the United States and across the world. The current pathology of progressive neurodegenerative tauopathies, such as Alzheimer's disease (AD), Pick's disease, frontotemporal dementia (FTD), and progressive supranuclear palsy, primarily revolves around phosphorylation and hyperphosphorylation of the tau protein. However, more recent evidence suggests acetylation of tau protein at lysine 280 may be a critical step in molecular pathology of these neurodegenerative diseases prior to the tau hyperphosphorylation. Secondary injury cascades such as oxidative stress, endoplasmic reticulum stress, and neuroinflammation contribute to lasting damage within the brain and can be induced by a number of different risk factors. These injury cascades funnel into a common pathway of early tau acetylation, which may serve as the catalyst for progressive degeneration. The post translational modification of tau can result in production of toxic oligomers, contributing to reduced solubility as well as aggregation and formation of neurofibrillary tangles, the hallmark of AD pathology. Chronic Traumatic Encephalopathy (CTE), caused by repetitive brain trauma is also associated with a hyperphosphorylation of tau. We postulated acetylation of tau at lysine 280 in CTE disease could be present prior to the hyperphosphorylation and tested this hypothesis in CTE pathologic specimens. We also tested for ac-tau 280 in early stage Alzheimer's disease (Braak stage 1). Histopathological examination using the ac tau 280 antibody was performed in three Alzheimer's cases and three CTE patients. Presence of ac-tau 280 was confirmed in all cases at early sites of disease manifestation. These findings suggest that tau acetylation may precede tau phosphorylation and could be the first "triggering" event leading to neuronal loss. To the best of our knowledge, this is the first study to identify acetylation of the tau protein in CTE. Prevention of tau acetylation could possibly serve as a novel target for stopping neurodegeneration before it fully begins. In this study, we highlight what is known about tau acetylation and neurodegeneration.
进行性神经退行性疾病困扰着美国乃至全世界数以百万计的人。目前，诸如阿尔茨海默病（AD）、匹克病、额颞叶痴呆（FTD）和进行性核上性麻痹等进行性神经退行性tau蛋白病的病理学主要围绕tau蛋白的磷酸化和过度磷酸化展开。然而，最近的证据表明，赖氨酸280处的tau蛋白乙酰化可能是这些神经退行性疾病分子病理学中tau蛋白过度磷酸化之前的关键步骤。氧化应激、内质网应激和神经炎症等继发性损伤级联反应会导致大脑内的持久损伤，并且可由多种不同的风险因素诱发。这些损伤级联反应汇聚成早期tau蛋白乙酰化的共同途径，这可能是进行性退化的催化剂。tau蛋白的翻译后修饰可导致有毒寡聚体的产生，导致溶解度降低以及神经原纤维缠结的聚集和形成，这是AD病理学的标志。由重复性脑外伤引起的慢性创伤性脑病（CTE）也与tau蛋白的过度磷酸化有关。我们推测CTE疾病中赖氨酸280处的tau蛋白乙酰化可能在过度磷酸化之前就已存在，并在CTE病理标本中验证了这一假设。我们还在早期阿尔茨海默病（Braak 1期）中检测了乙酰化tau 280。使用乙酰化tau 280抗体对3例阿尔茨海默病患者和3例CTE患者进行了组织病理学检查。在所有病例的疾病早期表现部位均证实了乙酰化tau 280的存在。这些发现表明，tau蛋白乙酰化可能先于tau蛋白磷酸化，并且可能是导致神经元丢失的首个“触发”事件。据我们所知，这是第一项在CTE中鉴定tau蛋白乙酰化的研究。预防tau蛋白乙酰化可能会成为在神经退行性变完全开始之前阻止其发生的新靶点。在本研究中，我们重点介绍了关于tau蛋白乙酰化和神经退行性变的已知情况。
