Assessing the Role of PLCG2*M28L Risk In A Novel Mouse Model Late‐Onset Alzheimer’s Disease

Abstract

AbstractBackgroundMODEL‐AD has developed and characterized novel mouse models that aim to better phenocopy human LOAD for preclinical testing. More than 40 different models carrying combinations of LOAD risk factors have been created and assessed for relevance to LOAD. In this study, we aim to determine the mechanisms by which variations in the phospholipase C gamma 2 (PLCG2) gene increase risk for LOAD.MethodsThe M28L variant in PLCG2 (PLCG2*M28L) was prioritized as a LOAD risk factor. Mice were generated by CRISPR/CAS9 introduction of Plcg2*M28L variant on to LOAD1 (B6.APOE4.Trem2*R47H) and transcriptional profiling of brain hemispheres from 12 months old mice was used to evaluate molecular effects of Plcg2*M28L. To evaluate the contribution of Plcg2*M28L to LOAD risk, mice where placed on control or high fat diet (HFD) to serve as an environmental driver of neuroinflammation. Female and male LOAD1.Plcg2*M28L and LOAD1 control mice are being characterized at 4 and 12 mos through the MODEL‐AD phenotyping pipeline, which includes in vivo imaging of brain perfusion and glycolytic metabolism, multi‐omics, fluid biomarkers, cognition, and neuropathology.ResultsLOAD1.Plcg2*M28L mice showed brain transcriptomic alignment at 12 mos to human LOAD, and was prioritized for deep phenotyping. LOAD1 mice on HFD showed significant regional reductions in brain glycolysis and increased perfusion relative to controls yielding an uncoupled phenotype. By contrast, LOAD1.Plcg2*M28L mice showed a little to no regional changes in brain glycolysis or perfusion and few uncoupled regions. Multi‐resolution connectomics revealed a decrease in cluster number and organization in LOAD1 but not LOAD1.Plcg2*M28L for both sexes fed HFD compared with control diets. By 12 mos, male and female LOAD1.Plcg2*M28L mice on HFD showed opposite changes in clustering coefficient, network degree, and network density, with males showing a decrease and females an increase relative to controls. Mice carrying Plcg2*M28L variants are also being phenotyping at 18 and 24 mos.ConclusionsData collected to date reveal Plcg2*M28L on a LOAD1 background showed fewer sex‐dependent change in metabolism, perfusion and uncoupling on HFD when compared to LOAD1. These data suggest that the Plcg2*M28L risk variant on the LOAD1 background may result in an attenuated TREM2 signaling.