A novel, humanized late‐onset Alzheimer’s disease mouse model expressing APOEe4, Trem2*R47H, and amyloid‐beta

Abstract

AbstractBackgroundLate‐onset Alzheimer’s disease (LOAD) is the most common form of dementia without an approved therapy. Transgenic overexpression animal models do not effectively produce the heterogeneity observed clinically in LOAD patients and thus are not ideal for therapy development. Hence, the Model Organism Development and Evaluation for Late‐onset AD (MODEL‐AD) Center is developing, characterizing, and distributing novel mouse models expressing humanized, clinically relevant risk factors. Analysis of aging LOAD2 mice that better phenocopy human disease will inform the further development of subsequent generations of models and reveal more appropriate molecular targets useful in the treatment of LOAD.MethodTwo risk factors of LOAD, APOEe4 and Trem2*R47H, were incorporated into C57BL/6J mice along with humanized amyloid‐beta to produce the LOAD2 model. Mice were aged up to 24 months. In some mice, high‐fat diet replaced normal mouse chow. An animal phenotyping pipeline was employed to qualify and align with neurodegenerative disease states and phenotypes observed in human patients. In vivo imaging in addition to behavior and wellness assays were performed, as were analyses of blood and brain tissue for risk‐factor‐related alterations in neuropathology, transcriptomics, metabolomics, and proteomics.ResultAged LOAD2 mice on high‐fat diet present altered cytokine profiles in the brain, and peripherally, however no overt hippocampal pathology nor differences in long‐term potentiation were observed. Expression of human amyloid did not yield plaque formation in 18‐month mice. High‐fat diet was a strong determinant during behavioral phenotyping. Correlation of transcriptional profiling with human AMP‐AD modules determined individual and synergistic effects between genetic and environmental risk factors compared to human data. Continuing efforts to dissect the clinically‐relevant downstream effects of sex, age, genotype, and diet in these animals remain.ConclusionThe MODEL‐AD consortium has established the LOAD2 mouse model to study the effects of genetic and environmental risk factors of LOAD. This strain serves as a platform for the incorporation of additional AD risk factors (both genetic and environmental) to more closely align phenotypes in the mouse to outcomes observed in the clinic. Here we show the evidence of emerging disease pathology in an animal model exposed to genetic and environmental risk factors.