在 Tau 病模型小鼠中 Tau 积累、小胶质细胞活化和脑萎缩的体内可视化
In Vivo Visualization of Tau Accumulation, Microglial Activation, and Brain Atrophy in a Mouse Model of Tauopathy rTg4510.
机构信息
National Institutes for Quantum and Radiological Science and Technology, Chiba, Japan.
Department of Neurology, Graduate School of Medicine, Chiba University, Chiba, Japan.
出版信息
J Alzheimers Dis. 2018;61(3):1037-1052. doi: 10.3233/JAD-170509.
BACKGROUND
Tau imaging using PET is a promising tool for the diagnosis and evaluation of tau-related neurodegenerative disorders, but the relationship among PET-detectable tau, neuroinflammation, and neurodegeneration is not yet fully understood.
OBJECTIVE
We aimed to elucidate sequential changes in tau accumulation, neuroinflammation, and brain atrophy by PET and MRI in a tauopathy mouse model.
METHODS
rTg4510 transgenic (tg) mice expressing P301L mutated tau and non-tg mice were examined with brain MRI and PET imaging (analyzed numbers: tg = 17, non-tg = 13; age 2.5∼14 months). As PET probes, [11C]PBB3 (Pyridinyl-Butadienyl-Benzothiazole 3) and [11C]AC-5216 were used to visualize tau pathology and 18-kDa translocator protein (TSPO) neuroinflammation. Tau pathology and microglia activation were subsequently analyzed by histochemistry.
RESULTS
PET studies revealed age-dependent increases in [11C]PBB3 and [11C]AC-5216 signals, which were correlated with age-dependent volume reduction in the forebrain on MRI. However, the increase in [11C]PBB3 signals reached a plateau at age 7 months, and therefore its significant correlation with [11C]AC-5216 disappeared after age 7 months. In contrast, [11C]AC-5216 showed a strong correlation with both age and volume reduction until age 14 months. Histochemical analyses confirmed the relevance of pathological tau accumulation and elevated TSPO immunoreactivity in putative microglia.
CONCLUSION
Our results showed that tau accumulation is associated with neuroinflammation and brain atrophy in a tauopathy mouse model. The time-course of the [11C]PBB3- and TSPO-PET finding suggests that tau deposition triggers progressive neuroinflammation, and the sequential changes can be evaluated in vivo in mouse brains.
背景
使用正电子发射断层扫描（PET）对 Tau 成像，是一种有前途的工具，可用于诊断和评估与 Tau 相关的神经退行性疾病，但 Tau 积聚、神经炎症和神经退行性变之间的关系尚不完全清楚。
目的
我们旨在通过 Tau 病小鼠模型的 PET 和 MRI 来阐明 Tau 积累、神经炎症和脑萎缩的顺序变化。
方法
用脑部 MRI 和 PET 成像检查 rTg4510 转基因（tg）小鼠（表达 P301L 突变 Tau）和非转基因（non-tg）小鼠（分析数量：tg=17，non-tg=13；年龄 2.5∼14 个月）。作为 PET 探针，[11C]PBB3（吡啶基-丁二烯基-苯并噻唑 3）和[11C]AC-5216 用于可视化 Tau 病理学和 18kDa 转位蛋白（TSPO）神经炎症。随后通过组织化学分析 Tau 病理学和小胶质细胞激活。
结果
PET 研究显示，[11C]PBB3 和[11C]AC-5216 信号随年龄增长呈依赖性增加，这与 MRI 上大脑前叶随年龄增长而体积减少相关。然而，[11C]PBB3 信号的增加在 7 个月时达到平台期，因此其与[11C]AC-5216 的显著相关性在 7 个月后消失。相比之下，[11C]AC-5216 与年龄和体积减少均呈强烈相关性，直至 14 个月。组织化学分析证实了病理性 Tau 积累与推定小胶质细胞中 TSPO 免疫反应性的相关性。
结论
我们的研究结果表明，在 Tau 病小鼠模型中，Tau 积累与神经炎症和脑萎缩有关。[11C]PBB3 和 TSPO-PET 结果的时间进程表明，Tau 沉积引发进行性神经炎症，并且可以在小鼠大脑中进行体内评估。
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