Longitudinal TSPO expression in tau transgenic P301S mice predicts increased tau accumulation and deteriorated spatial learning
Longitudinal TSPO expression in tau transgenic P301S mice predicts increased tau accumulation and deteriorated spatial learning
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DOI：
10.1186/s12974-020-01883-5
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发表时间：
2020-07-13
影响因子：
9.3
通讯作者：
Brendel, Matthias
中科院分区：
文献类型：
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作者：
Eckenweber, Florian;Medina-Luque, Jose;Brendel, Matthias
P301 S tau转基因小鼠在脑干、海马和新皮质中显示出神经元缠结的年龄依赖性积累，导致神经元损失和认知退化。然而，迄今为止，只有很少的文件中的tau小鼠模型中的神经炎症的作用。因此，我们分析了纵向小胶质细胞激活小动物18 kDa转运蛋白正电子发射断层扫描（TSPO μ PET）成像在体内，结合终端评估tau病理，空间学习，和脑葡萄糖代谢。方法对1.9、3.9和6.4个月大的转基因P301 S（n= 33）和野生型（n= 18）雌性小鼠进行F-GE-180 TSPO mu PET成像。在6.3-6.7个月时，我们在Morris水迷宫、F-18-氟脱氧葡萄糖（F-18-FDG）mu PET和AT 8 tau免疫组织化学中进行了行为测试。终末小胶质细胞免疫组织化学用于验证TSPO mu PET结果在体内，在脑干，皮质，小脑和海马中应用靶区域。我们将结果与淀粉样蛋白β小鼠模型的历史数据进行了比较。结果从1.9到6.4个月，P301 S小鼠所有靶区域中的TSPO表达呈指数增加，导致与野生型小鼠在6.4个月时相比的显著差异（+ 11- 23%，allp< 0.001），但是明显的小胶质细胞增生比我们在淀粉样蛋白β小鼠模型中的经验进行得更慢。与野生型组相比，AT 8阳性P301 S小鼠的空间学习和葡萄糖代谢在6.3-6.5个月时显著受损。TSPO表达的纵向增加预测了6.3-6.7个月时更大的tau积累和更少的空间学习表现。结论与β淀粉样蛋白小鼠模型相比，通过mu PET监测TSPO表达作为P301 S tau转基因小鼠中小胶质细胞活化的替代物表明了延迟的时间过程。小胶质细胞活化与结果参数的有害关联与淀粉样蛋白β小鼠模型中的早期数据相反。小胶质细胞对伴随淀粉样蛋白-β和tau蛋白过度表达的病理反应的贡献值得进一步研究。
Background P301S tau transgenic mice show age-dependent accumulation of neurofibrillary tangles in the brainstem, hippocampus, and neocortex, leading to neuronal loss and cognitive deterioration. However, there is hitherto only sparse documentation of the role of neuroinflammation in tau mouse models. Thus, we analyzed longitudinal microglial activation by small animal 18 kDa translocator protein positron-emission-tomography (TSPO mu PET) imaging in vivo, in conjunction with terminal assessment of tau pathology, spatial learning, and cerebral glucose metabolism. Methods Transgenic P301S (n= 33) and wild-type (n= 18) female mice were imaged by(18)F-GE-180 TSPO mu PET at the ages of 1.9, 3.9, and 6.4 months. We conducted behavioral testing in the Morris water maze,F-18-fluordesoxyglucose (F-18-FDG) mu PET, and AT8 tau immunohistochemistry at 6.3-6.7 months. Terminal microglial immunohistochemistry served for validation of TSPO mu PET results in vivo, applying target regions in the brainstem, cortex, cerebellum, and hippocampus. We compared the results with our historical data in amyloid-beta mouse models. Results TSPO expression in all target regions of P301S mice increased exponentially from 1.9 to 6.4 months, leading to significant differences in the contrasts with wild-type mice at 6.4 months (+ 11-23%, allp< 0.001), but the apparent microgliosis proceeded more slowly than in our experience in amyloid-beta mouse models. Spatial learning and glucose metabolism of AT8-positive P301S mice were significantly impaired at 6.3-6.5 months compared to the wild-type group. Longitudinal increases in TSPO expression predicted greater tau accumulation and lesser spatial learning performance at 6.3-6.7 months. Conclusions Monitoring of TSPO expression as a surrogate of microglial activation in P301S tau transgenic mice by mu PET indicates a delayed time course when compared to amyloid-beta mouse models. Detrimental associations of microglial activation with outcome parameters are opposite to earlier data in amyloid-beta mouse models. The contribution of microglial response to pathology accompanying amyloid-beta and tau over-expression merits further investigation.