In Vivo Visualization of Tau Accumulation, Microglial Activation, and Brain Atrophy in a Mouse Model of Tauopathy rTg4510
In Vivo Visualization of Tau Accumulation, Microglial Activation, and Brain Atrophy in a Mouse Model of Tauopathy rTg4510
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DOI：
10.3233/jad-170509
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发表时间：
2018-01-01
影响因子：
4
通讯作者：
Sahara, Naruhiko
中科院分区：
文献类型：
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作者：
Ishikawa, Ai;Tokunaga, Masaki;Sahara, Naruhiko
背景：应用正电子发射计算机断层扫描(PET)技术对tau相关神经退行性疾病的诊断和评估是一种很有前途的工具，但PET可检测到的tau与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PET和MRI来阐明tau在tau蓄积、神经炎症和脑萎缩中的顺序变化。方法：对表达P301L突变tau的rTg4510转基因(TG)小鼠和非Tg转基因小鼠进行脑MRI和PET成像(分析数字：Tg=17，非Tg=13；年龄2.5，类似14个月)。以[C-11]PBB3(吡啶-丁二烯-苯并噻唑3)和[C-11]AC-5216为PET探针，观察tau病理和18 kDa转位蛋白(TSPO)神经炎症。结果：PET研究显示[C-11]PBB3和[C-11]AC-5216信号随年龄增长而增加，这与MRI上前脑体积随年龄增长而减小有关。然而，[C-11]PBB3信号的增加在7个月龄时达到平台期，因此它与[C-11]AC-5216的显著相关性在7个月龄后消失。相反，在14个月之前，[C-11]AC-5216显示出与年龄和体积减少都有很强的相关性。组织化学分析证实了病理性tau蓄积与TSPO免疫反应性升高的相关性。结论：我们的结果显示tau蓄积与tau病小鼠模型的神经炎症和脑萎缩有关。[C-11]PBB3-和TSPO-PET研究结果的时间进程表明，tau的沉积触发了进行性神经炎症，并且可以在体内评估小鼠大脑的连续变化。
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 similar to 14 months). As PET probes, [C-11] PBB3 (Pyridinyl-Butadienyl-Benzothiazole 3) and [C-11] 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 [C-11] PBB3 and [C-11] AC-5216 signals, which were correlated with age-dependent volume reduction in the forebrain on MRI. However, the increase in [C-11] PBB3 signals reached a plateau at age 7 months, and therefore its significant correlation with [C-11] AC-5216 disappeared after age 7 months. In contrast, [C-11] 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 [C-11] PBB3- and TSPO-PET finding suggests that tau deposition triggers progressive neuroinflammation, and the sequential changes can be evaluated in vivo in mouse brains.