Sacher, Christian, Blume, Tanja, Beyer, Leonie, Peters, Finn, Eckenweber, Floria, Sgobio, Carmelo, Deussing, Maximilian, Albert, Nathalie, Unterrainer, Marcus, Lindner, Simon, Gildehaus, Franz-Joseph, von Ungern-Sternberg, Barbara, Brzak, Irena, Neumann, Ulf, Saito, Takashi, Saido, Takomi, Bartenstein, Peter, Rominger, Axel, Herms, Jochen and Brendel, Matthias (2019) Longitudinal in vivo PET assessment of cerebral β-Amyloid deposition and glial activation in knock-in mice non-overexpressing β-Amyloid precursor protein. Journal of nuclear medicine : JNM, 58 (2). ISSN 1535-5667; 0161-5505

Abstract

Ziel/Aim: Overexpression of ß-amyloid (Aß) precursor protein in common transgenic Aß mouse models of Alzheimer's disease (AD) potentially hampers their translational potential. The novel APP-NL-G-F Aß mouse model circumvents this issue by a knockin and is supposed to be highly valuable for Aß targeting treatment trials. The aim of this study was to establish serial PET as an important tool for therapy monitoring in APP-NL-G-F mice. Methodik/Methods: APP-NL-G-F mice (homozygous (HOM) N = 20; heterozygous (HET) N = 21) and age-matched wild-type (WT) mice (N = 12) were investigated longitudinally from 2.5 to 10 months of age by F-18-florbetaben Aß PET and F-18-GE180 18kDa translocator protein (TSPO) PET. Cortical and hippocampal standardized-uptake-value-ratios (SUVR) were analyzed over time. Voxel-wise analyses were performed using statistical parametric mapping. All mice passed behavioral testing by water maze after their final PET scan. Immunohistochemical quantification of fibrillar Aß and activated microglia as well as protein quantification of Aß , Aß and Trem2 served for validation of PET results. Ergebnisse/Results: HOM APP-NL-G-F mice indicated raising SUVR in cortex and hippocampus for both Aß and TSPO PET (all p < 0.05), whereas HET mice only revealed a not significant Aß increase and no cerebral glial activation. Voxel-wise analyses increased sensitivity and revealed first significant clusters of Aß deposition and microglial activation in HOM mice at 5 months of age. Immunohistochemical and biochemical findings correlated strongly with in vivo PET data. Escape latency was significantly elevated in HOM APP-NL-G-F mice when compared to WT and correlated with TSPO PET. Schlussfolgerungen/Conclusions: First longitudinal PET in APP-NL-G-F knock-in mice facilitated monitoring of amyloidogenesis and neuroinflammation in HOM mice whereas the method is not sensitive enough for detection of minor changes in HET animals. The combination of PET with behavioral tasks in APP-NL-G-F treatment trails will provide important insights towards preclinical drug development.

Item Type:	Article
Date Deposited:	27 Aug 2019 00:45
Last Modified:	27 Aug 2019 00:45
URI:	https://oak.novartis.com/id/eprint/38837