Nonphysiologic overexpression of amyloid-β (Aβ) precursor protein in common transgenic Aβ 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 Aβ-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 ¹⁸F-florbetaben Aβ PET and ¹⁸F-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 Aβ 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 Aβ (+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 Aβ 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.

在常见的阿尔茨海默病转基因Aβ小鼠模型中，淀粉样β（Aβ）前体蛋白的非生理性过表达可能会阻碍其翻译潜能。新型App ^NL-GF小鼠整合了突变敲入，可能为针对Aβ的治疗试验提供改善的阿尔茨海默病模型。我们旨在在App ^NL-GF小鼠中建立淀粉样变性和神经炎症的系列小动物PET，作为治疗监测的工具。方法： 对2.5只至10 mo年龄的App ^NL-GF小鼠（20只纯合和21只异种）和12只与年龄匹配的野生型小鼠进行纵向研究，研究对象为¹⁸ F-florbetabenAβPET和^18只F-GE-180 18-kDa转运蛋白（TSPO）PET。使用统计参数映射对SUV比率图像进行Voxelwise分析。在最后一次扫描后，所有小鼠都进行了莫里斯水迷宫的空间学习测试。通过免疫组织化学和生物化学对纤维状Aβ和活化的小胶质细胞的定量用于验证PET结果。结果：导水管周围的灰色显示为两种示踪剂的合适伪参照组织。纯合App ^NL-GF小鼠从2.5到10个月大时，Aβ（+ 9.1％，+ 3.8％）和TSPO（+ 19.8％，+ 14.2％）PET的皮质和海马SUV比率升高（所有P <0.05 ），而杂合App ^NL-GF小鼠没有显示出随年龄的显着变化。在纯合子小鼠中，Aβ沉积和小胶质细胞激活的明显体素簇出现在5月龄。免疫组化和生化发现与PET数据密切相关。与10 mo龄的野生型相比，纯合App ^NL-GF小鼠的水迷宫逃逸潜伏期显着增加，并且与高TSPO结合有关。结论：App ^NL-GF敲入小鼠的纵向PET能够监测纯合小鼠的淀粉样蛋白生成和神经炎症，但对杂合动物的微小变化不敏感。PET与App ^NL-GF中的行为任务的结合 治疗试验有望为临床前药物开发提供重要的见识。