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

Abstract

Nonphysiologic overexpression of amyloid-β (Aβ) precursor protein in common transgenic Aβ mouse models of Alzheimer disease likely hampers their translational potential. The novel <i>App</i>^{<i>NL-G-F</i>} 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 <i>App</i>^{<i>NL-G-F</i>} mice as a tool for therapy monitoring. <b>Methods:</b><i>App</i>^{<i>NL-G-F</i>} 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. <b>Results:</b> The periaqueductal gray emerged as a suitable pseudo reference tissue for both tracers. Homozygous <i>App</i>^{<i>NL-G-F</i>} 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 <i>P</i> < 0.05), whereas heterozygous <i>App</i>^{<i>NL-G-F</i>} 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 <i>App</i>^{<i>NL-G-F</i>} mice compared with wild-type at 10 mo of age and was associated with high TSPO binding. <b>Conclusion:</b> Longitudinal PET in <i>App</i>^{<i>NL-G-F</i>} 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 <i>App</i>^{<i>NL-G-F</i>} treatment trials is poised to provide important insights in preclinical drug development.