Department of Nuclear Medicine, University Hospital of Munich, LMU Munich, 81377, Munich, Germany.
Center of Neuropathology and Prion Research, University Hospital of Munich, LMU Munich, 81377, Munich, Germany.
J Neuroinflammation. 2020 Jul 13;17(1):208. doi: 10.1186/s12974-020-01883-5.
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 μPET) imaging in vivo, in conjunction with terminal assessment of tau pathology, spatial learning, and cerebral glucose metabolism.
Transgenic P301S (n = 33) and wild-type (n = 18) female mice were imaged by F-GE-180 TSPO μPET at the ages of 1.9, 3.9, and 6.4 months. We conducted behavioral testing in the Morris water maze, F-fluordesoxyglucose (F-FDG) μPET, and AT8 tau immunohistochemistry at 6.3-6.7 months. Terminal microglial immunohistochemistry served for validation of TSPO μPET results in vivo, applying target regions in the brainstem, cortex, cerebellum, and hippocampus. We compared the results with our historical data in amyloid-β mouse models.
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%, all p < 0.001), but the apparent microgliosis proceeded more slowly than in our experience in amyloid-β 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.
Monitoring of TSPO expression as a surrogate of microglial activation in P301S tau transgenic mice by μPET indicates a delayed time course when compared to amyloid-β mouse models. Detrimental associations of microglial activation with outcome parameters are opposite to earlier data in amyloid-β mouse models. The contribution of microglial response to pathology accompanying amyloid-β and tau over-expression merits further investigation.
P301S tau 转基因小鼠表现出脑干、海马体和新皮层中与年龄相关的神经纤维缠结积累，导致神经元丧失和认知恶化。然而，tau 小鼠模型中的神经炎症作用迄今仅有零星的报道。因此，我们通过小动物 18 kDa 转位蛋白正电子发射断层扫描（TSPO μPET）成像进行了体内纵向小胶质细胞激活分析，结合 tau 病理学、空间学习和大脑葡萄糖代谢的终末评估。
在 1.9、3.9 和 6.4 月龄时，对 P301S（n = 33）和野生型（n = 18）雌性小鼠进行 F-GE-180 TSPO μPET 成像。在 6.3-6.7 月龄时，我们在 Morris 水迷宫、F-氟脱氧葡萄糖（F-FDG）μPET 和 AT8 tau 免疫组化中进行行为测试。末端小胶质细胞免疫组化用于验证体内 TSPO μPET 结果，在脑干、皮层、小脑和海马体中应用目标区域。我们将结果与我们在淀粉样蛋白-β小鼠模型中的历史数据进行了比较。
P301S 小鼠所有目标区域的 TSPO 表达从 1.9 个月到 6.4 个月呈指数增长，导致在 6.4 个月时与野生型小鼠的差异具有统计学意义（+ 11-23%，均 p < 0.001），但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展更慢。与野生型组相比，6.3-6.5 月龄时 AT8 阳性 P301S 小鼠的空间学习和葡萄糖代谢显著受损。6.3-6.7 月龄时 TSPO 表达的纵向增加预测了更大的 tau 积累和更差的空间学习表现。
通过 μPET 监测 P301S tau 转基因小鼠中 TSPO 表达作为小胶质细胞激活的替代指标，与淀粉样蛋白-β小鼠模型相比，其时间进程延迟。小胶质细胞激活与结局参数之间的有害关联与淀粉样蛋白-β小鼠模型中的早期数据相反。小胶质细胞反应对淀粉样蛋白-β和 tau 过表达相关病理学的贡献值得进一步研究。
