Uncovering Disease Mechanisms in a Novel Mouse Model Expressing Humanized APOEε4 and Trem2*R47H

• DOI: 10.3389/fnagi.2021.735524
• Publication Date: 2021-10-13T17:17:36Z
• Authors: Kevin P. Kotredes; Adrian Oblak; Ravi S. Pandey; Peter Bor-Chian Lin; Dylan Garceau; Harriet Williams; Asli Uyar; Rita O’Rourke; Sarah O’Rourke; Cynthia Ingraham; Daria Bednarczyk; Melisa Belanger; Zackary Cope; Kate E. Foley; Benjamin A. Logsdon; Lara M. Mangravite; Stacey J. Sukoff ...; Paul R. Territo; Gregory W. Carter; Michael Sasner; Bruce T. Lamb; Gareth R. Howell
• Keywords: TREM2; Apolipoprotein E; Humanized mouse

Late-onset Alzheimer’s disease (AD; LOAD) is the most common human neurodegenerative disease, however, availability and efficacy of disease-modifying interventions severely lacking. Despite exceptional efforts to understand progression via legacy amyloidogenic transgene mouse models, focus on translation with innovative strains that better model complexity AD required accelerate development future treatment modalities. LOAD within population a polygenic environmentally influenced many risk factors acting in concert produce processes parallel those often muted by early aggressive aggregate formation popular strains. In addition extracellular deposits amyloid plaques inclusions microtubule-associated protein tau, also defined synaptic/neuronal loss, vascular deficits, neuroinflammation. These underlying need be defined, how progresses age, compared human-relevant outcomes. To create more translatable MODEL-AD (Model Organism Development Evaluation for AD) groups are identifying integrating disease-relevant, humanized gene sequences from public databases beginning APOEε4 Trem2*R4 7H, two powerful present populations. Mice expressing endogenous, 7H were extensively aged assayed using multi-disciplined phenotyping approach associated relative pathology. Robust analytical pipelines measured behavioral, transcriptomic, metabolic, neuropathological phenotypes cross-sectional cohorts hallmarks at all life stages. vivo PET/MRI neuroimaging revealed regional alterations glycolytic metabolism perfusion. Transcriptional profiling RNA-Seq brain hemispheres identified sex age as main sources variation between genotypes including age-specific enrichment AD-related processes. Similarly, was strongest determinant behavioral change. absence plaque formation, not observed this strain. However, sensitized baseline additional alleles environmental modifications already appended, dataset initial strain serves an important role establishing individual effects interaction strong genetic host.