Involvement of Oligodendrocytes in Tau Seeding and Spreading in Tauopathies
Involvement of Oligodendrocytes in Tau Seeding and Spreading in Tauopathies
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DOI：
10.3389/fnagi.2019.00112
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发表时间：
2019-05-28
影响因子：
4.8
通讯作者：
Antonio del Rio, Jose
中科院分区：
文献类型：
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作者：
Ferrer, Isidro;Aguilo Garcia, Meritxell;Antonio del Rio, Jose
简介：将表达野生或突变 tau 的转基因小鼠和野生型 (WT) 小鼠的 tau 蛋白病变获得的脑匀浆的不同灰质区域脑内接种后，就会发生人 tau 播种和扩散。然而，人们对白质接种后 tau 蛋白的传播知之甚少。 目的：本研究旨在了解在胼胝体中单侧接种散发性阿尔茨海默病 (AD)、原发性年龄相关 tau 病（部分：神经元 4Rtau 和 3Rtau）、纯衰老相关 tau 蛋白的匀浆后，tau 蛋白播种和相关细胞的模式 星形胶质病（ARTAG：星形胶质细胞 4Rtau 伴刺状星形胶质细胞 TSA）、球状神经胶质 tau 病（GGT：4Rtau 伴神经元 tau 以及星形胶质细胞和少突胶质细胞、GAls 和 GOls 中分别含有特定 tau 包涵体）、进行性核上性麻痹（PSP：4Rtau 伴 神经元包涵体、簇状星形胶质细胞和卷曲体）、Pick 病（PiD：3Rtau，神经元中具有特征性 Pick 小体和含有纤维状星形胶质细胞的 tau），以及与 P301L 突变相关的额颞叶变性（FTLD-P301L：4Rtau 家族性 tau 病）。方法：成年 WT 小鼠 用来自上述tau蛋白病的肌氨酰不溶性级分或肌氨酰可溶性级分单侧接种于外侧胼胝体；接种后4至7个月处死小鼠。将大脑固定在多聚甲醛中，包埋在石蜡中并进行免疫组织化学处理。结果：Tau 播种发生在同侧胼胝体中，并且在对侧胼胝体中也检测到。在类似于卷曲体和线状的少突胶质细胞中发现了磷酸化 tau 沉积物。此外，tau 沉积物与活性（磷酸化）tau 激酶 p38 和 ERK 1/2 共定位，表明小鼠 tau 存在活性 tau 磷酸化。在任何情况下均未观察到 TSA、GAls、GOls、簇状星形胶质细胞和含有 tau 的纤维状星形胶质细胞。 Tau 沉积物通常与轻微的髓磷脂破坏以及在接种每次 tau 病的肌氨酰不溶性组分 6 个月后同侧胼胝体中存在小的 PLP1 免疫反应性小球和点有关。结论：人 tau 在 WT 小鼠胼胝体中的播种和扩散发生在少突胶质细胞中，从而 支持少突胶质细胞病在 tau 病白质中 tau 播种和扩散中发挥作用的观点。线或少突胶质细胞沉积物的优势的轻微差异表明tau蛋白病之间tau蛋白播种和传播能力的疾病差异。
Introduction: Human tau seeding and spreading occur following intracerebral inoculation into different gray matter regions of brain homogenates obtained from tauopathies in transgenic mice expressing wild or mutant tau, and in wild-type (WT) mice. However, little is known about tau propagation following inoculation in the white matter.Objectives: The present study is geared to learning about the patterns of tau seeding and cells involved following unilateral inoculation in the corpus callosum of homogenates from sporadic Alzheimer's disease (AD), primary age-related tauopathy (PART: neuronal 4Rtau and 3Rtau), pure aging-related tau astrogliopathy (ARTAG: astroglial 4Rtau with thorn-shaped astrocytes TSAs), globular glial tauopathy (GGT: 4Rtau with neuronal tau and specific tau inclusions in astrocytes and oligodendrocytes, GAls and GOls, respectively), progressive supranuclear palsy (PSP: 4Rtau with neuronal inclusions, tufted astrocytes and coiled bodies), Pick's disease (PiD: 3Rtau with characteristic Pick bodies in neurons and tau containing fibrillar astrocytes), and frontotemporal lobar degeneration linked to P301L mutation (FTLD-P301L: 4Rtau familial tauopathy).Methods: Adult WT mice were inoculated unilaterally in the lateral corpus callosum with sarkosyl-insoluble fractions or with sarkosyl-soluble fractions from the mentioned tauopathies; mice were killed from 4 to 7 months after inoculation. Brains were fixed in paraformaldehyde, embedded in paraffin and processed for immunohistochemistry.Results: Tau seeding occurred in the ipsilateral corpus callosum and was also detected in the contralateral corpus callosum. Phospho-tau deposits were found in oligodendrocytes similar to coiled bodies and in threads. Moreover, tau deposits co-localized with active (phosphorylated) tau kinases p38 and ERK 1/2, suggesting active tau phosphorylation of murine tau. TSAs, GAls, GOls, tufted astrocytes, and tau-containing fibrillar astrocytes were not seen in any case. Tau deposits were often associated with slight myelin disruption and the presence of small PLP1-immunoreactive globules and dots in the ipsilateral corpus callosum 6 months after inoculation of sarkosyl-insoluble fractions from every tauopathy.Conclusions: Seeding and spreading of human tau in the corpus callosum of WT mice occurs in oligodendrocytes, thereby supporting the idea of a role of oligodendrogliopathy in tau seeding and spreading in the white matter in tauopathies. Slight differences in the predominance of threads or oligodendroglial deposits suggest disease differences in the capacity of tau seeding and spreading among tauopathies.