Department of Translational Science and Molecular Medicine, College of Human Medicine, Michigan State University, Grand Rapids, Michigan, MI, United States.
Department of Neurology, University of Michigan, Ann Arbor, Michigan, MI, United States.
Curr Alzheimer Res. 2018;15(12):1086-1095. doi: 10.2174/1567205015666180813152043.
The lack of diagnostic tools and disease-modifying treatments against Alzheimer's disease (AD) and related disorders, collectively known as tauopathies, has led to a socioeconomic burden of epidemic proportion. Proteomics approaches can be used to identify novel proteome changes that could help us understand the pathogenesis of tau-related pathological hallmarks and/or cellular stress responses associated with tauopathy. These studies, however, need to be conducted taking into consideration brain region specificity and stage of neurodegeneration in order to provide insights about the pathological role of the identified proteins.
We used a tauopathy mouse model (JNPL3) that expresses human tau bearing a P301L mutation and develops motor impairment, the severity of which correlates with the increased accumulation of pathological tau. Tissue was dissected from asymptomatic and severely motor impaired JNPL3 mice as well as non-transgenic littermate controls and subjected to two-dimensional gel electrophoresis. Differentially abundant protein spots were identified by tandem mass spectrometry. Postmortem mild cognitive impairment (MCI), AD and normal aging controls were used to validate the pathological significance of the identified protein.
Ezrin was identified as a protein that is upregulated in tau-mediated neurodegeneration. We demonstrate that Ezrin protein abundance increased in JNPL3 mice preceded motor impairment and was sustained in severely motor impaired mice. Ezrin expression was also increased in the temporal cortex of MCI and AD patients.
The results demonstrate that increased Ezrin protein abundance changes are associated with the early stages of neurodegeneration in tauopathy models and human disease. Understanding the role of Ezrin in tauopathies such as AD may provide new insights for targeting tau-mediated neurodegeneration.
目前缺乏针对阿尔茨海默病（AD）和相关疾病（统称为 tau 病）的诊断工具和疾病修饰治疗方法，这导致了具有流行比例的社会经济负担。蛋白质组学方法可用于鉴定新的蛋白质组变化，这有助于我们了解与 tau 相关的病理特征和/或与 tau 病相关的细胞应激反应的发病机制。然而，这些研究需要考虑大脑区域特异性和神经退行性变的阶段，以便提供有关鉴定蛋白的病理作用的见解。
我们使用了一种 tau 病小鼠模型（JNPL3），该模型表达了携带 P301L 突变的人 tau，并且表现出运动障碍，其严重程度与病理性 tau 的积累增加相关。从无症状和严重运动障碍的 JNPL3 小鼠以及非转基因同窝对照中分离组织，并进行二维凝胶电泳。通过串联质谱鉴定差异丰富的蛋白质斑点。使用死后轻度认知障碍（MCI）、AD 和正常衰老对照来验证鉴定蛋白的病理意义。
Ezrin 被鉴定为在 tau 介导的神经退行性变中上调的蛋白质。我们证明 Ezrin 蛋白丰度的增加发生在 JNPL3 小鼠运动障碍之前，并在严重运动障碍的小鼠中持续存在。Ezrin 的表达在 MCI 和 AD 患者的颞叶皮层中也增加了。
这些结果表明，Ezrin 蛋白丰度的增加变化与 tau 病模型和人类疾病的神经退行性变的早期阶段有关。了解 Ezrin 在 AD 等 tau 病中的作用可能为靶向 tau 介导的神经退行性变提供新的见解。
