Longitudinal PET Monitoring of Amyloidosis and Microglial Activation in a Second Generation Amyloid-beta Mouse Model

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