Regional vulnerability and spreading of hyperphosphorylated tau in seeded mouse brain
Regional vulnerability and spreading of hyperphosphorylated tau in seeded mouse brain
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DOI：
10.1016/j.nbd.2019.03.010
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发表时间：
2019-07-01
影响因子：
6.1
通讯作者：
De Vos, Winnok H.
中科院分区：
文献类型：
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作者：
Detrez, Jan R.;Maurin, Herve;De Vos, Winnok H.
我们利用全脑显微镜来绘制完整的、清除的小鼠大脑中过度磷酸化的tau的渐进沉积。我们发现过度磷酸化的tau蛋白在衰老tau蛋白的大脑中的三维扩散模式。P301L小鼠模型与AD患者观察到的不相似。在CA1区域注射合成或患者来源的tau原纤维导致更忠实的扩散模式。atlas引导的体积分析显示连接体依赖于注射部位的扩散，并且还显示了直接解剖连接之外的过度磷酸化的tau沉积。在注射原纤维的大脑中，我们还发现了一个持续的杆状和肿胀的小胶质细胞亚群。此外，我们发现，通过颅内联合给药，以及在较小程度上通过反复全身给药靶向tau微管结合结构域的抗体，可以减少过度磷酸化的tau负荷。因此，靶向植入和tau病理分期的结合可以全面评估区域脆弱性，并具有作为临床前药物验证工具的潜力。
We have exploited whole brain microscopy to map the progressive deposition of hyperphosphorylated tau in intact, cleared mouse brain. We found that the three-dimensional spreading pattern of hyperphosphorylated tau in the brain of an aging Tau.P301L mouse model did not resemble that observed in AD patients. Injection of synthetic or patient-derived tau fibrils in the CA1 region resulted in a more faithful spreading pattern. Atlas-guided volumetric analysis showed a connectome-dependent spreading from the injection site and also revealed hyperphosphorylated tau deposits beyond the direct anatomical connections. In fibril-injected brains, we also detected a persistent subpopulation of rod-like and swollen microglia. Furthermore, we showed that the hyperphosphorylated tau load could be reduced by intracranial co-administration of, and to a lesser extent, by repeated systemic dosing with an antibody targeting the microtubule-binding domain of tau. Thus, the combination of targeted seeding and in tote staging of tau pathology allowed assessing regional vulnerability in a comprehensive manner, and holds potential as a preclinical drug validation tool.