Proteomic Profiling of Mouse Brains Exposed to Blast-Induced Mild Traumatic Brain Injury Reveals Changes in Axonal Proteins and Phosphorylated Tau.
Proteomic Profiling of Mouse Brains Exposed to Blast-Induced Mild Traumatic Brain Injury Reveals Changes in Axonal Proteins and Phosphorylated Tau.
复制标题
DOI：
10.3233/jad-180726
复制
发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Xia W
中科院分区：
文献类型：
--
作者：
Chen M;Song H;Cui J;Johnson CE;Hubler GK;DePalma RG;Gu Z;Xia W
阿尔茨海默病（AD）是最常见的痴呆症形式，其特点是两种病理特征：含tau的神经原纤维缠结和含淀粉样蛋白-β (Aβ)的神经性斑块。本研究的目的是了解轻度创伤性脑损伤（mTBI）相关的脑蛋白质组学变化和tau相关的生化适应可能导致ad样神经变性。我们发现，暴露于82-kPa低强度露天爆炸后3和24 h收集的小鼠大脑中磷酸化tau蛋白（p-tau）和p-tau/tau比值均显著增加。在爆炸后24 h和7 d采用简单神经不对称损伤评估（SNAP）试验观察动物神经功能缺损，7 d采用银染色观察轴突/树突变性。采用液相色谱-质谱法（LC-MS/MS）分析等压质量标签标记的脑组织，进行相对蛋白定量。蛋白质组学和生物信息学分析的结果表明，轴突和突触蛋白在相关通路上的改变，包括但不限于黑质发育、皮质细胞骨架组织和突触囊泡胞吐，表明爆炸诱导的mTBI可能导致轴突损伤。在脑损伤中发现的改变蛋白中，微管相关蛋白1B、静钙素、神经丝、肌动蛋白结合蛋白、髓鞘碱性蛋白、钙/钙调素依赖性蛋白激酶和突触蛋白I是mTBI引起的通路改变的代表性蛋白。因此，TBI诱导磷酸化tau蛋白升高，这是AD患者大脑中发现的一种病理特征，并改变了许多神经生理过程，支持了爆炸诱导的mTBI作为AD发病机制的危险因素的观点。基于LC/ ms的分析提供了候选靶点/途径，可以为未来的治疗开发进行探索。
Alzheimer’s disease (AD), the most prevalent form of dementia, is characterized by two pathological hallmarks: Tau-containing neurofibrillary tangles and amyloid-β protein (Aβ)-containing neuritic plaques. The goal of this study is to understand mild traumatic brain injury (mTBI)-related brain proteomic changes and tau-related biochemical adaptations that may contribute to AD-like neurodegeneration. We found that both phosphorylated tau (p-tau) and the ratio of p-tau/tau were significantly increased in brains of mice collected at 3 and 24 h after exposure to 82-kPa low-intensity open-field blast. Neurological deficits were observed in animals at 24 h and 7 days after the blast using Simple Neuroassessment of Asymmetric imPairment (SNAP) test, and axon/dendrite degeneration was revealed at 7 days by silver staining. Liquid chromatography-mass spectrometry (LC-MS/MS) was used to analyze brain tissue labeled with isobaric mass tags for relative protein quantification. The results from the proteomics and bioinformatic analysis illustrated the alterations of axonal and synaptic proteins in related pathways, including but not being limited to substantia nigra development, cortical cytoskeleton organization, and synaptic vesicle exocytosis, suggesting a potential axonal damage caused by blast-induced mTBI. Among altered proteins found in brains suffering blast, microtubule-associated protein 1B, stathmin, neurofilaments, actin binding proteins, myelin basic protein, calcium/calmodulin-dependent protein kinase, and synaptotagmin I were representative ones involved in altered pathways elicited by mTBI. Therefore, TBI induces elevated phospho-tau, a pathological feature found in brains of AD, and altered a number of neurophysiological processes, supporting the notion that blast-induced mTBI as a risk factor contributes to AD pathogenesis. LC/MS-based profiling has presented candidate target/pathways that could be explored for future therapeutic development.