In Vivo Imaging Biomarkers of Neurotoxicity (S07-4)

Existing animal models have been shown to have poor translational relevance for Alzheimer’s disease (AD).   In the MODEL-AD Center, our approach is to improve recapitulating AD by the combination of mouse models expressing knocked-in genetic risk variants associated with late-onset AD combined with environmental risk factors and aging to enable improved translational validity. Here we present a phenotypic characterization of a novel mouse model based on the combination of genetic and environmental risk factors at an extended age.  A mouse model expressing two genetic risk factors (APOE4 and Trem2*R47H) was fed a high-fat, high-sugar diet (“HFD”) and analyzed from 4 to 24 months of age for neuropathology, biomarkers, transcriptomics and metabolomics, and in vivo imaging.  By 12 months of age, we detected increases in insoluble Aβ42 in brain, Aβ42: Aβ40 in plasma, proinflammatory cytokines, and NfL in CSF.  Glucose uptake and cerebral perfusion changes were also detected with in vivo imaging with FDG and PTSM .  By 18months, we showed a decrease in hippocampal neuron number and serum metabolomic signatures that mimic AD patients.  Dense core neuritic plaques were not detected even at 24 months of age.  We demonstrate that a combining genetic risk, environmental risk and aging may recapitulate the early stages of AD prior to significant amyloid deposition in an animal model.  Therefore, this approach may have utility in the evaluation of potential prophylactic treatments for AD.