Send to

Choose Destination
J Nucl Med. 2019 Dec;60(12):1787-1793. doi: 10.2967/jnumed.119.227322. Epub 2019 Jul 13.

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

Author information

Department of Nuclear Medicine, University Hospital of Munich, LMU Munich, Munich Germany.
DZNE-German Center for Neurodegenerative Diseases, Munich, Germany.
Neuroscience, Novartis Institutes for BioMedical Research (NIBR), Basel, Switzerland.
Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science, Saitama, Japan.
Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
Department of Nuclear Medicine, Inselspital, University Hospital Bern, Bern, Switzerland; and.
Center of Neuropathology and Prion Research, University of Munich, Munich, Germany.
Department of Nuclear Medicine, University Hospital of Munich, LMU Munich, Munich Germany


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.


Alzheimer disease; AppNL-G-F; microglia; spatial learning; β-amyloid

[Available on 2020-06-01]

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center