Kanaan Nicholas M, Grabinski Tessa
Department of Translational Neuroscience, College of Human Medicine, Michigan State University, Grand Rapids, MI, United States.
Neuroscience Program, Michigan State University, East Lansing, MI, United States.
Front Mol Neurosci. 2021 Apr 27;14:607303. doi: 10.3389/fnmol.2021.607303. eCollection 2021.
Tau is a microtubule-associated protein for which the physiological functions remain a topic of vigorous investigation. Additionally, tau is a central player in the pathogenesis of several diseases such as Alzheimer's disease and several frontotemporal dementias. A critical variable to understanding tau in physiological and disease contexts is its normal localization within cells of the adult CNS. Tau is often described as an axon-specific (or enriched) and neuron-specific protein with little to no expression in glial cells, all of which are untrue. Understanding normal tau distribution also impacts interpretation of experimental results and hypotheses regarding its role in disease. Thus, we set out to help clarify the normal localization of tau in the adult CNS of middle-aged rats and rhesus macaque using the hippocampus as a representative brain structure. The physiological concentration of tau in the rat hippocampus was 6.6 μM and in white matter was 3.6 μM as determined by quantitative sandwich ELISAs. We evaluated the cellular localization of tau using multiple tau-specific antibodies with epitopes to different regions, including Tau1, Tau5, Tau7, R1, and two novel primate-specific antibodies NT9 and NT15. In the rat and monkey, tau was localized within the somatodendritic and axonal compartments, as well as a subset of neuronal nuclei. Semi-quantitative fluorescence intensity measurements revealed that depending on the specific reagent used the somatodendritic tau is relatively equal to, higher than, or lower than axonal tau, highlighting differential labeling of tau with various antibodies despite its distribution throughout the neuron. Tau was strongly expressed in mature oligodendrocytes and displayed little to no expression in oligodendrocyte precursor cells, astrocytes or microglia. Collectively, the data indicate tau is ∼3 - 7 μM under physiological conditions, is not specifically enriched in axons, and is normally found in both neurons and mature oligodendrocytes in the adult CNS. The full landscape of tau distribution is not revealed by all antibodies suggesting availability of the epitopes is different within specific neuronal compartments. These findings set the stage for better understanding normal tau distributions and interpreting data regarding the presence of tau in different compartments or cell types within disease conditions.
tau是一种与微管相关的蛋白质，其生理功能仍是一个深入研究的课题。此外，tau在几种疾病（如阿尔茨海默病和几种额颞叶痴呆）的发病机制中起着核心作用。在生理和疾病背景下理解tau的一个关键变量是其在成年中枢神经系统细胞内的正常定位。tau通常被描述为一种轴突特异性（或富集）且神经元特异性的蛋白质，在胶质细胞中几乎不表达或无表达，但这些说法都是不正确的。理解tau的正常分布也会影响对实验结果以及关于其在疾病中作用的假设的解读。因此，我们着手以海马体作为代表性脑结构，帮助阐明中年大鼠和恒河猴成年中枢神经系统中tau的正常定位。通过定量夹心酶联免疫吸附测定法确定，大鼠海马体中tau的生理浓度为6.6 μM，白质中为3.6 μM。我们使用了多种针对tau不同区域表位的特异性抗体，包括Tau1、Tau5、Tau7、R1以及两种新的灵长类特异性抗体NT9和NT15，来评估tau的细胞定位。在大鼠和猴子中，tau定位于树突体和轴突区室以及一部分神经元细胞核内。半定量荧光强度测量显示，根据所使用的特定试剂不同，树突体tau相对等于、高于或低于轴突tau，这突出了尽管tau分布于整个神经元，但不同抗体对其标记存在差异。tau在成熟少突胶质细胞中强烈表达，在少突胶质前体细胞、星形胶质细胞或小胶质细胞中几乎不表达或无表达。总体而言，数据表明在生理条件下tau浓度约为3 - 7 μM，并非特异性富集于轴突，且在成年中枢神经系统的神经元和成熟少突胶质细胞中均正常存在。并非所有抗体都能揭示tau分布的全貌，这表明特定神经元区室内表位的可及性不同。这些发现为更好地理解tau的正常分布以及解读疾病状态下不同区室或细胞类型中tau存在的数据奠定了基础。
