Systematic phenotyping and characterization of the 3xTg-AD mouse model of Alzheimer's Disease

Javonillo, D. I.; Tran, K. M.; Phan, J.; Hingco, E.; Kramar, E. A.; da Cunha, C.; Forner, S.; Kawauchi, S.; Neumann, J.; Banh, C. E.; Hyunh, M.; Matheos, D. P.; Rezai, N.; Alcantara, J. A.; Mortazavi, A.; Wiid, M. A.; Tenner, A. J.; MacGregor, G.; Green, K. N.; LaFerla, F. M.

doi:10.1101/2021.10.01.462640

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bioRxiv · 10.1101/2021.10.01.462640

Systematic phenotyping and characterization of the 3xTg-AD mouse model of Alzheimer's Disease

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Abstract

Animal models of disease are valuable resources for investigating pathogenic mechanisms and potential therapeutic interventions. However, for complex disorders such as Alzheimers disease (AD), the generation and availability of innumerous distinct animal models present unique challenges to AD researchers and hinder the success of useful therapies. Here, we conducted an in-depth analysis of the 3xTg-AD mouse model of AD across its lifespan to better inform the field of the various pathologies that appear at specific ages, and comment on drift that has occurred in the development of pathology in this line since its development 20 years ago. This modern characterization of the 3xTg-AD model includes an assessment of impairments in behavior, cognition, and long-term potentiation followed by quantification of amyloid beta (A{beta}) plaque burden and neurofibrillary tau tangles, biochemical levels of A{beta} and tau protein, and neuropathological markers such as gliosis and accumulation of dystrophic neurites. We also present a novel comparison of the 3xTg-AD model with the 5xFAD model using the same deep-phenotyping characterization pipeline. The results from these analyses are freely available via the AD Knowledge Portal (https://admodelexplorer.synapse.org). Our work demonstrates the utility of a characterization pipeline that generates robust and standardized information relevant to investigating and comparing disease etiologies of current and future models of AD. Contribution to the Field StatementAlzheimers Disease (AD) is an age-related neurodegenerative disorder characterized by progressive memory impairments and affects more than 30 million individuals worldwide. Using animal models of AD, researchers have elucidated disease progression and hallmark pathologies that may underpin the memory impairments seen in patients. However, therapeutic targets have failed to translate successfully from animal studies to human clinical trials, prompting a reassessment of the development, use, and interpretation of data acquired using the innumerous AD animal models available to researchers. To address these shortcomings, we have developed a robust and reproducible modern characterization of pathologies within current and future animal models of AD to better assess distinct pathologies that arise at specific brain regions and ages of different models. Using the popular 3xTg-AD mouse, we demonstrate the utility of these deep-phenotyping analyses and highlight the drift that affected development of pathologies in this line over the past two decades. Utilizing this same systematic characterization, we also perform a direct comparison with 5xFAD mice, another popular animal model of AD. The robust and standardized data generated from these systematic deep-phenotyping analyses are available for broad use by the AD research community to assess, compare, and determine appropriate animal models of AD.

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Javonillo, D. I., Tran, K. M., Phan, J., Hingco, E., Kramar, E. A., da Cunha, C., Forner, S., Kawauchi, S., Neumann, J., Banh, C. E., Hyunh, M., Matheos, D. P., Rezai, N., Alcantara, J. A., Mortazavi, A., Wiid, M. A., Tenner, A. J., MacGregor, G., Green, K. N., LaFerla, F. M.. 2021-10-02. Systematic phenotyping and characterization of the 3xTg-AD mouse model of Alzheimer's Disease. https://doi.org/10.1101/2021.10.01.462640

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