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

Sacher, Christian; Blume, Tanja; Beyer, Leonie; Peters, Finn; Eckenweber, Florian; Sgobio, Carmelo; Deussing, Maximilian; Albert, Nathalie L; Unterrainer, Marcus; Lindner, Simon; Gildehaus, Franz-Josef; von Ungern-Sternberg, Barbara; Brzak, Irena; Neumann, Ulf; Saito, Takashi; Saido, Takaomi C; Bartenstein, Peter; Rominger, Axel; Herms, Jochen and Brendel, Matthias (2019). Longitudinal PET Monitoring of Amyloidosis and Microglial Activation in a Second-Generation Amyloid-β Mouse Model. The journal of nuclear medicine, 60(12), pp. 1787-1793. Society of Nuclear Medicine and Molecular Imaging 10.2967/jnumed.119.227322

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Radiology, Neuroradiology and Nuclear Medicine (DRNN) > Clinic of Nuclear Medicine

UniBE Contributor:

Rominger, Axel Oliver

Subjects:

600 Technology > 610 Medicine & health

ISSN:

0161-5505

Publisher:

Society of Nuclear Medicine and Molecular Imaging

Language:

English

Submitter:

Andrea Stettler

Date Deposited:

18 Dec 2019 10:47

Last Modified:

18 Dec 2019 10:53

Publisher DOI:

10.2967/jnumed.119.227322

PubMed ID:

31302633

Uncontrolled Keywords:

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

BORIS DOI:

10.7892/boris.137052

URI:

https://boris.unibe.ch/id/eprint/137052

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