Filip Thomas, Mairinger Severin, Neddens Joerg, Sauberer Michael, Flunkert Stefanie, Stanek Johann, Wanek Thomas, Okamura Nobuyuki, Langer Oliver, Hutter-Paier Birgit, Kuntner Claudia
Preclinical Molecular Imaging, AIT Austrian Institute of Technology GmbH, 2444, Seibersdorf, Austria.
Department of Biomedical Research, Medical University Vienna, Vienna, Austria.
Alzheimers Res Ther. 2021 Oct 16;13(1):175. doi: 10.1186/s13195-021-00916-2.
To better understand the etiology and pathomechanisms of Alzheimer's disease, several transgenic animal models that overexpress human tau or human amyloid-beta (Aβ) have been developed. In the present study, we generated a novel transgenic rat model by cross-breeding amyloid precursor protein (APP) rats with tau rats. We characterized this model by performing positron emission tomography scans combined with immunofluorescent labeling and cerebrospinal fluid analyses.
APP/Tau rats were generated by cross-breeding male McGill-R-Thy1-APP transgenic rats with female hTau-40/P301L transgenic rats. APP/Tau double transgenic rats and non-transgenic (ntg) littermates aged 7, 13, and 21 months were subjected to dynamic [C] PiB scan and dynamic [F]THK-5317 scans. For regional brain analysis, a template was generated from anatomical MR images of selected animals, which was co-registered with the PET images. Regional analysis was performed by application of the simplified reference tissue model ([C]PiB data), whereas [F]THK-5317 data were analyzed using a 2-tissue compartment model and Logan graphical analysis. In addition, immunofluorescent labeling (tau, amyloid) and cerebrospinal fluid analyses were performed.
[C]PiB binding potential (BP) and [F]THK-5317 volume of distribution (V) showed an increase with age in several brain regions in the APP/Tau group but not in the ntg control group. Immunohistochemical analysis of brain slices of PET-scanned animals revealed a positive correlation between Aβ labeling and [C]PiB regional BP. Tau staining yielded a trend towards higher levels in the cortex and hippocampus of APP/Tau rats compared with ntg littermates, but without reaching statistical significance. No correlation was found between tau immunofluorescence labeling results and the respective [F]THK-5317 V values.
We thoroughly characterized a novel APP/Tau rat model using combined PET imaging and immunofluorescence analysis. We observed an age-related increase in [C]PiB and [F]THK-5317 binding in several brain regions in the APP/Tau group but not in the ntg group. Although we were able to reveal a positive correlation between amyloid labeling and [C]PiB regional brain uptake, we observed relatively low human tau and amyloid fibril expression levels and a somewhat unstable brain pathology which questions the utility of this animal model for further studies.
为了更好地理解阿尔茨海默病的病因和发病机制，已经开发了几种过表达人tau或人淀粉样β蛋白（Aβ）的转基因动物模型。在本研究中，我们通过将淀粉样前体蛋白（APP）大鼠与tau大鼠杂交，构建了一种新型转基因大鼠模型。我们通过结合正电子发射断层扫描、免疫荧光标记和脑脊液分析对该模型进行了表征。
通过将雄性麦吉尔-R-Thy1-APP转基因大鼠与雌性hTau-40/P301L转基因大鼠杂交，培育出APP/Tau大鼠。对7、13和21月龄的APP/Tau双转基因大鼠和非转基因（ntg）同窝仔鼠进行动态[C]PiB扫描和动态[F]THK-5317扫描。对于脑区分析，从选定动物的解剖磁共振图像生成模板，并将其与PET图像进行配准。区域分析采用简化参考组织模型（[C]PiB数据）进行，而[F]THK-5317数据则采用双组织室模型和洛根图形分析进行分析。此外，还进行了免疫荧光标记（tau、淀粉样蛋白）和脑脊液分析。
在APP/Tau组的几个脑区中，[C]PiB结合潜能（BP）和[F]THK-5317分布容积（V）随年龄增加，而在ntg对照组中则没有。对PET扫描动物的脑切片进行免疫组织化学分析发现，Aβ标记与[C]PiB区域BP之间存在正相关。与ntg同窝仔鼠相比，APP/Tau大鼠皮质和海马区的tau染色有升高趋势，但未达到统计学意义。tau免疫荧光标记结果与相应的[F]THK-5317 V值之间未发现相关性。
我们通过联合PET成像和免疫荧光分析对一种新型APP/Tau大鼠模型进行了全面表征。我们观察到APP/Tau组几个脑区中[C]PiB和[F]THK-5317结合随年龄增加，而ntg组则没有。虽然我们能够揭示淀粉样蛋白标记与[C]PiB脑区摄取之间的正相关，但我们观察到人类tau和淀粉样纤维表达水平相对较低，且脑病理学有些不稳定，这对该动物模型在进一步研究中的实用性提出了质疑。
