Hallmarks of late‐onset Alzheimer's disease in a humanized mouse model: Development of new models and analysis methods/screening studies/platforms. (7th December 2020)

• Record Type: Journal Article
• Authors: Kotredes, Kevin P.; Preuss, Christoph; Pandey, Ravi S.; Territo, Paul R.; Oblak, Adrian L.; Kaddurah‐Daouk, Rima F.; Arnold, Matthias; Seyfried, Nicholas T.; Duong, Duc; Williams, Harriet M.; Lamb, Bruce T.; Rizzo, Stacey J. Sukoff; Carter, Gregory W.; Sasner, Michael; Howell, Gareth
• Is Part Of: Alzheimer's & dementia. Volume 16(2020)Supplement 2
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-12-07
• Subjects: Alzheimer's disease -- Periodicals; Alzheimer Disease -- Periodicals; Dementia -- Periodicals; Démence; Maladie d'Alzheimer; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.83
• DOI: 10.1002/alz.045162
• Languages: English
• ISSNs: 1552-5260

Abstract

Abstract: Background: If progress is to be made in the pursuit to cure Alzheimer's Disease (AD), researchers and clinicians require better resources to understand this heterogenous pathology. Thus, the Model Organism Development and Evaluation for Late‐onset AD consortium (MODEL‐AD) is charged with creating, defining, and distributing novel mouse models of late‐onset AD (LOAD) carrying human‐relevant risk factors. Characterization of these variants in aging mice will reveal more appropriate disease pathways useful in the treatment of LOAD. Method: APOEe4 and Trem2*R47H variants, two primary risk factors of LOAD, were incorporated into the genome of C57BL/6J (B6J) mice. Cohorts of B6J. APOE4/Trem2*R47H mice were established on multiple sites and aged to 4, 8, 12, and 24 months. Behavior and wellness assays measured vigor, activity, coordination, cognition, and biometrics. In vivo MRI and PET cerebral imaging, to measure perfusion and metabolism, were also completed, as were post‐mortem analyses of blood chemistry, neuropathology, transcriptomics, metabolomics, and proteomics. Result: As expected, mice expressing the humanized APOEe4 allele showed decreased plasma lipoprotein levels across all time points. Further, a novel splicing event was observed in mice expressing the Trem2 *R47H variant, leading to a reduction of allele expression. In the absence of additional environmental or genetic risk factors, B6J. APOE4/Trem2*R47H mice did not display penetrant behavioral phenotypes, but did exhibit decreased survival probabilities by 24 months. Analysis of 6‐month‐old animals revealed differences in plasma metabolite levels and in brain proteomes compared to controls. Neuropathology analysis in brain tissue is in progress, as are cytokine panels in brain homogenates and plasma. Conclusion: The MODEL‐AD consortium has established B6J. APOE4/Trem2*R47H model to study the effects of two strong risk factors of LOAD. This strain serves as a platform for the further incorporation of human risk alleles of AD to more closely align phenotypes in the mouse to outcomes observed in the clinic. In accordance, the effect of a high fat diet is being evaluated in B6J. APOE4/Trem2*R47H mice. Ultimately, strains carrying combinations of risk factors that more closely align with human disease will be incorporated into the pre‐clinical testing core of MODEL‐AD to assess the potential of prioritized compounds to treat AD.