Deep phenotyping of the 5XFAD model: IU/JAX/PITT MODEL‐AD center: Development of new models and analysis methods/novel assays and technologies. (7th December 2020) - Oblak, Adrian L.
Abstract: Background: Alzheimer's disease (AD) is the most common form of dementia without an effective treatment. Animal models of AD have been valuable tools to understand familial or early onset AD, but to date have not been predictive for translational research. The Model Organism Development and Evaluation for Late‐onset AD (MODEL‐AD) Center is developing, validating, and distributing novel mouse models of late‐onset AD (LOAD) that can be used to develop novel therapeutics. Using the 5XFAD model of early onset AD, we have established pipelines to characterize models across multiple sites using biochemistry, histology, functional assays, in vivo MRI and PET imaging, and Serial Two‐Photon (STP) tomography whole brain imaging. Methods: At designated time points, animals were subjected to the following assays: Functional ‐ behavioral testing paradigms, and in vivo MRI and PET scanning followed by secondary validation with autoradiography. Biochemistry/Histology ‐ mice were sacrificed, perfused, and tissue harvested, with half of the brain frozen and the other half fixed. On frozen tissue samples we performed bulk RNA‐seq. On fixed tissue samples, we assessed AD relevant changes using the following stains and antibodies: X34 (plaques and NFTs), Lamp1 (dystrophic neurites), Iba1 (microglia). STP Whole Brain Imaging ‐ on additional fixed tissue samples we performed whole brain imaging and regional analysis of Methoxy‐X04 labeled plaques using the TissueCyte® imaging platform. Results: Combined assessment of the 5XFAD model revealed systematic neurodegenerative changes in the mouse brain. Multiple data sets including histology, biochemistry, RNA‐seq, transcriptomics, in vivo imaging, and STP whole brain analysis show differences throughout disease progression. Conclusions: We utilized the well characterized 5XFAD model of AD to develop an integrated pipeline for deep phenotyping of novel mouse models of AD. This pipeline combines novel functional and anatomical assays across sites to track the ontology of AD progression, and targeted understanding of the molecular, biochemical and functional progression of AD pathology. Together, this pipeline provides a novel platform for greater understanding of LOAD mouse models and potential therapeutic approaches for AD.