Institute for Regenerative Medicine, University of Zurich, Zurich, Switzerland.
Zentrum für Neurowissenschaften Zürich (ZNZ), Zurich, Switzerland.
Eur J Nucl Med Mol Imaging. 2022 Jun;49(7):2137-2152. doi: 10.1007/s00259-022-05708-w. Epub 2022 Feb 7.
Abnormal tau accumulation within the brain plays an important role in tauopathies such as Alzheimer's disease and frontotemporal dementia. High-resolution imaging of tau deposits at the whole-brain scale in animal disease models is highly desired.
We approached this challenge by non-invasively imaging the brains of P301L mice of 4-repeat tau with concurrent volumetric multi-spectral optoacoustic tomography (vMSOT) at ~ 115 μm spatial resolution using the tau-targeted pyridinyl-butadienyl-benzothiazole derivative PBB5 (i.v.). In vitro probe characterization, concurrent vMSOT and epi-fluorescence imaging of in vivo PBB5 targeting (i.v.) was performed in P301L and wild-type mice, followed by ex vivo validation using AT-8 antibody for phosphorylated tau.
PBB5 showed specific binding to recombinant K18 tau fibrils by fluorescence assay, to post-mortem Alzheimer's disease brain tissue homogenate by competitive binding against [C]PBB3 and to tau deposits (AT-8 positive) in post-mortem corticobasal degeneration and progressive supranuclear palsy brains. Dose-dependent optoacoustic and fluorescence signal intensities were observed in the mouse brains following i.v. administration of different concentrations of PBB5. In vivo vMSOT brain imaging of P301L mice showed higher retention of PBB5 in the tau-laden cortex and hippocampus compared to wild-type mice, as confirmed by ex vivo vMSOT, epi-fluorescence, multiphoton microscopy, and immunofluorescence staining.
We demonstrated non-invasive whole-brain imaging of tau in P301L mice with vMSOT system using PBB5 at a previously unachieved ~ 115 μm spatial resolution. This platform provides a new tool to study tau spreading and clearance in a tauopathy mouse model, foreseeable in monitoring tau targeting putative therapeutics.
脑内异常tau 聚集在tau 病（如阿尔茨海默病和额颞叶痴呆）中起重要作用。非常希望在动物疾病模型中以高分辨率对整个大脑范围的 tau 沉积物进行高分辨率成像。
我们通过使用针对 tau 的吡啶基-丁二烯-苯并噻唑衍生物 PBB5（iv.）在 115μm 左右的空间分辨率下对 P301L 小鼠的大脑进行非侵入性的 4 重复 tau 多光谱光声断层扫描（vMSOT），从而解决了这一挑战。在 P301L 和野生型小鼠中进行了体外探针特性、体内 PBB5 靶向（iv.）的 vMSOT 和共聚焦荧光成像，然后使用针对磷酸化 tau 的 AT-8 抗体进行了离体验证。
荧光测定法显示 PBB5 与重组 K18 tau 原纤维具有特异性结合，与竞争性结合 [C]PBB3 的死后阿尔茨海默病脑组织匀浆以及死后皮质基底节变性和进行性核上性麻痹大脑中的 tau 沉积物（AT-8 阳性）具有特异性结合。静脉注射不同浓度的 PBB5 后，在小鼠大脑中观察到光声和荧光信号强度呈剂量依赖性增加。与野生型小鼠相比，P301L 小鼠静脉注射 PBB5 后，tau 负荷皮质和海马中的 PBB5 保留量更高，这一点通过离体 vMSOT、共聚焦荧光、多光子显微镜和免疫荧光染色得到了证实。
我们使用 PBB5 在以前未达到的 115μm 空间分辨率下，通过 vMSOT 系统证明了 P301L 小鼠的 tau 进行了非侵入性的全脑成像。该平台为研究 tau 病小鼠模型中的 tau 扩散和清除提供了一种新工具，有望用于监测针对 tau 的潜在治疗药物。
