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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

1
Department of Nuclear Medicine, University Hospital of Munich, LMU Munich, Munich Germany.
2
DZNE-German Center for Neurodegenerative Diseases, Munich, Germany.
3
Neuroscience, Novartis Institutes for BioMedical Research (NIBR), Basel, Switzerland.
4
Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science, Saitama, Japan.
5
Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
6
Department of Nuclear Medicine, Inselspital, University Hospital Bern, Bern, Switzerland; and.
7
Center of Neuropathology and Prion Research, University of Munich, Munich, Germany.
8
Department of Nuclear Medicine, University Hospital of Munich, LMU Munich, Munich Germany matthias.brendel@med.uni-muenchen.de.

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 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.

KEYWORDS:

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

PMID:
31302633
PMCID:
PMC6894380
[Available on 2020-06-01]
DOI:
10.2967/jnumed.119.227322

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