A quantitative in vivo imaging platform for tracking pathological tau depositions and resultant neuronal death in a mouse model
A quantitative in vivo imaging platform for tracking pathological tau depositions and resultant neuronal death in a mouse model
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DOI：
10.1007/s00259-022-05898-3
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发表时间：
2022-07-08
影响因子：
9.1
通讯作者：
Higuchi, Makoto
中科院分区：
文献类型：
--
作者：
Kimura, Taeko;Ono, Maiko;Higuchi, Makoto
目的tau纤维的沉积涉及多种神经退行性疾病，包括阿尔茨海默病，并且tau病理学及其对神经元存活的影响的精确评估对于在有和没有潜在疗法的情况下追求神经退行性tau发病机制是至关重要的。我们的目的是建立一个体内成像系统，以定量tau积累与正电子发射断层扫描（PET）和脑萎缩与体积MRI rTg 4510转基因小鼠模型神经退行性tau蛋白病。方法总共91只rTg 4510和非转基因对照小鼠在不同年龄（1.8-12.3个月）接受了tau放射性示踪剂F-18-PM-PBB 3的PET和MRI。以小脑为参照，用标准摄取值比（SUVR）和分布容积比（DVR）估算靶区的放射性示踪剂结合。还对来自扫描动物的脑切片进行组织学染色，以研究成像-神经病理学相关性。结果rTg 4510小鼠新皮层、海马和纹状体中F-18-PM-PBB 3在40-60 min的SUVR与DVR一致，在4-5月龄左右与对照值显著不同，并分别与年龄和局部体积呈进行性和负相关。新皮质SUVR还与尸检分析中PM-PBB 3荧光、Gallyas-Braak银浸渍和抗磷酸化tau抗体标记的tau内含物的丰度相关。体内和离体F-18-PM-PBB 3结合被非放射性PM-PBB 3阻断。F-18-PM-PBB 3产生比其祖先C-11-PBB 3大1.6倍的tau成像动态范围。结论我们的成像平台能够量化tau沉积和随之而来的神经元损失，并可能适用于候选抗tau和神经保护药物的评价。
Purpose Depositions of tau fibrils are implicated in diverse neurodegenerative disorders, including Alzheimer's disease, and precise assessments of tau pathologies and their impacts on neuronal survival are crucial for pursuing the neurodegenerative tau pathogenesis with and without potential therapies. We aimed to establish an in vivo imaging system to quantify tau accumulations with positron emission tomography (PET) and brain atrophy with volumetric MRI in rTg4510 transgenic mice modeling neurodegenerative tauopathies. Methods A total of 91 rTg4510 and non-transgenic control mice underwent PET with a tau radiotracer, F-18-PM-PBB3, and MRI at various ages (1.8-12.3 months). Using the cerebellum as reference, the radiotracer binding in target regions was estimated as standardized uptake value ratio (SUVR) and distribution volume ratio (DVR). Histopathological staining of brain sections derived from scanned animals was also conducted to investigate the imaging-neuropathology correlations. Results F-18-PM-PBB3 SUVR at 40-60 min in the neocortex, hippocampus, and striatum of rTg4510 mice agreed with DVR, became significantly different from control values around 4-5 months of age, and progressively and negatively correlated with age and local volumes, respectively. Neocortical SUVR also correlated with the abundance of tau inclusions labeled with PM-PBB3 fluorescence, Gallyas-Braak silver impregnation, and anti-phospho-tau antibodies in postmortem assays. The in vivo and ex vivo F-18-PM-PBB3 binding was blocked by non-radioactive PM-PBB3. F-18-PM-PBB3 yielded a 1.6-fold greater dynamic range for tau imaging than its ancestor, C-11-PBB3. Conclusion Our imaging platform has enabled the quantification of tau depositions and consequent neuronal loss and is potentially applicable to the evaluation of candidate anti-tau and neuroprotective drugs.