Longitudinal PET Monitoring of Amyloidosis and Microglial Activation in a Second-Generation Amyloid-β Mouse Model
Longitudinal PET Monitoring of Amyloidosis and Microglial Activation in a Second-Generation Amyloid-β Mouse Model
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DOI：
10.2967/jnumed.119.227322
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发表时间：
2019-12-01
影响因子：
9.3
通讯作者：
Brendel, Matthias
中科院分区：
文献类型：
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作者：
Sacher, Christian;Blume, Tanja;Brendel, Matthias
在常见的阿尔茨海默病转基因 Aβ 小鼠模型中，淀粉样蛋白 -β (Aβ) 前体蛋白的非生理性过度表达可能会阻碍其转化潜力。新型 App(NL-G-F) 小鼠结合了突变敲入，可能为 A β 靶向治疗试验提供改进的阿尔茨海默病模型。我们的目标是在 App(NL-G-F) 小鼠中建立淀粉样变性和神经炎症的连续小动物 PET，作为治疗监测的工具。方法：使用 F-18-florbetaben A beta PET 和 F-18-GE-180 18-kDa 易位蛋白 (TSPO) PET 对 App(NL-G-F) 小鼠（20 只纯合小鼠和 21 只异质小鼠）和 12 只年龄匹配的野生型小鼠（2.5 至 10 个月）进行纵向研究。使用统计参数映射对 SUV 比率图像进行体素分析。所有小鼠在最后一次扫描后都接受了莫里斯水迷宫空间学习测试。通过免疫组织化学和生物化学对原纤维 Aβ 和活化的小胶质细胞进行定量，以验证 PET 结果。结果：导水管周围灰质成为两种示踪剂的合适伪参考组织。纯合子 App(NL-G-F) 小鼠在 2.5 至 10 月龄期间，皮层和海马的 Aβ SUV 比率 (+9.1%, +3.8%) 和 TSPO (+19.8%, +14.2%) PET 呈上升趋势（均 P < 0.05），而杂合子 App(NL-G-F) 小鼠则没有表现出随年龄的显着变化。纯合小鼠中显着的 Aβ 沉积和小胶质细胞激活体素簇出现在 5 个月龄时。免疫组织化学和生化结果与 PET 数据密切相关。与 10 月龄野生型小鼠相比，纯合 App(NL-G-F) 小鼠的水迷宫逃逸潜伏期显着延长，并且与高 TSPO 结合相关。结论：App(NL-G-F) 敲入小鼠中的纵向 PET 能够监测纯合子小鼠的淀粉样蛋白生成和神经炎症，但对杂合子动物的微小变化不敏感。 App(NL-G-F) 治疗试验中 PET 与行为任务的结合有望为临床前药物开发提供重要见解。
Nonphysiologic overexpression of amyloid-beta (A beta) precursor protein in common transgenic A beta mouse models of Alzheimer disease likely hampers their translational potential. The novel App(NL-G-F) mouse incorporates a mutated knock-in, potentially presenting an improved model of Alzheimer disease for A beta-targeting treatment trials. We aimed to establish serial small-animal PET of amyloidosis and neuroinflammation in App(NL-G-F) mice as a tool for therapy monitoring. Methods: App(NL-G-F) mice (20 homozygous and 21 heterogeneous) and 12 age-matched wild-type mice were investigated longitudinally from 2.5 to 10 mo of age with F-18-florbetaben A beta PET and F-18-GE-180 18-kDa translocator protein (TSPO) PET. Voxelwise analysis of SUV ratio images was performed using statistical parametric mapping. All mice underwent a Morris water maze test of spatial learning after their final scan. Quantification of fibrillar A beta and activated microglia by immunohistochemistry and biochemistry served for validation of the PET results. Results: The periaqueductal gray emerged as a suitable pseudo reference tissue for both tracers. Homozygous App(NL-G-F) mice had a rising SUV ratio in cortex and hippocampus for A beta (+9.1%, +3.8%) and TSPO (+19.8%, +14.2%) PET from 2.5 to 10 mo of age (all P < 0.05), whereas heterozygous App(NL-G-F) mice did not show significant changes with age. Significant voxelwise clusters of A beta deposition and microglial activation in homozygous mice appeared at 5 mo of age. Immunohistochemical and biochemical findings correlated strongly with the PET data. Water maze escape latency was significantly elevated in homozygous App(NL-G-F) mice compared with wild-type at 10 mo of age and was associated with high TSPO binding. Conclusion: Longitudinal PET in App(NL-G-F) knock-in mice enables monitoring of amyloidogenesis and neuroinflammation in homozygous mice but is insensitive to minor changes in heterozygous animals. The combination of PET with behavioral tasks in App(NL-G-F) treatment trials is poised to provide important insights in preclinical drug development.