Quantitative Brain Positron Emission Tomography in Female 5XFAD Alzheimer Mice: Pathological Features and Sex-Specific Alterations

Abstract

Successful back-translating clinical biomarkers and molecular imaging methods of Alzheimer's disease (AD), including positron emission tomography (PET), are very valuable for the evaluation of new therapeutic strategies and increase the quality of preclinical studies. 18F-Fluorodeoxyglucose (FDG)–PET and 18F-Florbetaben–PET are clinically established biomarkers capturing two key pathological features of AD. However, the suitability of 18F-FDG– and amyloid–PET in the widely used 5XFAD mouse model of AD is still unclear. Furthermore, only data on male 5XFAD mice have been published so far, whereas studies in female mice and possible sex differences in 18F-FDG and 18F-Florbetaben uptake are missing. The aim of this study was to evaluate the suitability of 18F-FDG– and 18F-Florbetaben–PET in 7-month-old female 5XFAD and to assess possible sex differences between male and female 5XFAD mice. We could demonstrate that female 5XFAD mice showed a significant reduction in brain glucose metabolism and increased cerebral amyloid deposition compared with wild type animals, in accordance with the pathology seen in AD patients. Furthermore, we showed for the first time that the hypometabolism in 5XFAD mice is gender-dependent and more pronounced in female mice. Therefore, these results support the feasibility of small animal PET imaging with 18F-FDG- and 18F-Florbetaben in 5XFAD mice in both, male and female animals. Moreover, our findings highlight the need to account for sex differences in studies working with 5XFAD mice.

Abnormal [18F]NIFENE binding in transgenic 5xFAD mouse model of Alzheimer's disease: In vivo PET/CT imaging studies of α4β2* nicotinic acetylcholinergic receptors and in vitro correlations with Aβ plaques

“…The 5xFAD mice expressing Aβ plaques were found to be an excellent model to examine potential alterations in α4β2* nAChRs. The presence of Aβ plaques in these mice were confirmed in these mice using [ 124/125 I]IBETA and anti-Aβ IHC (Nguyen et al, 2022) and [ 18 F]flotaza (Kaur et al, 2021) and were consistent with the findings of [ 18 F]florbetaben (Boulter et al, 2021). In vitro binding of [ 125 I]IBETA and [ 124 I]IBETA in transgenic 5xFAD mouse model for Aβ plaques was high in the frontal cortex, anterior cingulate, thalamus, and hippocampus, which were regions of high Aβ accumulation, with very little binding in the cerebellum (ratio of brain regions to cerebellum was >5).…”

“…At the age of 18 months, the mice develop extensive Aβ deposits and serve as good models of advanced human AD (Forner et al., 2021; Oblak et al., 2021). PET imaging studies in the 5xFAD transgenic mice have been carried out using various PET probes including Aβ plaque imaging [ 18 F]florbetaben (Boulter et al., 2021; Jullienne et al., 2022). Our recent findings using brain slices in vitro autoradiography and in vivo PET confirmed Aβ plaque accumulation in 5xFAD mice using the imaging agent [ 124/125 I]IBETA (Nguyen et al., 2022).…”

Brain Metabolic Network Covariance and Aging in a Mouse Model of Alzheimer’s Disease

“…Indeed, Bouter et al showed that early-age 5XFAD females exhibit lower brain metabolic uptake compared to controls. This global decrease likely overshadows any sex-dependent developmental differences in glucose metabolism [37]. Second, when comparing weighted distributions across genotype, we found a significant difference in edge weights (both positive and negative) between 12-month female WT and 5XFAD group networks (Figure 2F).…”

Brain metabolic network covariance and aging in a mouse model of Alzheimer's disease

“…showed that early‐age 5XFAD females exhibit lower brain metabolic uptake compared to controls. This global decrease likely overshadows any sex‐dependent developmental differences in glucose metabolism 37 . Second, when comparing weighted distributions across genotype, we found a significant difference in edge weights (both positive and negative) between 12‐month female WT and 5XFAD group networks (Figure 2F).…”