UC Irvine MODEL-AD

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ABSTRACT The goal of the University of California, Irvine MODEL-AD U54 Center is to develop novel mouse models of late- onset Alzheimer’s disease (LOAD), to deeply phenotype these and to make all data and mouse strains available to enable researchers to select the optimal mouse model and timepoints for therapeutic and intervention testing, as well as testing of hypotheses concerning mechanisms of LOAD. During the past five years, we have generated and deeply phenotyped mice with one component of our base genetic platform in which the Aß region of the App gene was converted from the rodent to the human sequence, and we have recently introduced the second component, a humanized MAPT (TAU) locus produced via gene-replacement. We have also used CRISPR and genome replacement to model and validate nine GWAS identified LOAD risk loci and have characterized mice with each of these both on a wild-type and 5xFAD background to determine their effects on plaque generation and damage exerted on the brain in response to pathology. In this continuation, we will use the results of these analyses to identify the combinations of LOAD risk variants most likely to phenocopy LOAD and introduce them on two complementary hAb-KI, hTAU, hAPOE4 platform lines, designed to mimic sub-types of AD that have been recently defined. To ensure translationability, we have an expanded focus on biomarkers and alignment with human phenotypes. To that end we have established a new Core – the Neuroimaging and neurovascular core (NIVC), which will provide brain imaging modalities currently employed in human AD subjects to align phenotypes in our mice with human disease progression. We have also expanded our fluid biomarker analysis efforts to include CSF, as well as plasma lipidomics and metabolomics to be compared to human AD plasma signatures. Similarly, our bioinformatics and data management efforts have been expanded to include single cell and nucleus RNA-seq and ATAC-seq, as well as spatial transcriptomics to enable alignment of data from our models with human AD signatures, but also to understand the mechanisms underlying disease progression in our mice. We are utilizing a comprehensive approach to evaluate our mice across their lifespans, which includes behavioral/cognitive assessment, electrophysiological analysis, super-resolution synaptic imaging, neuroimaging, bulk and single-cell RNA-seq, single cell level spatial transcriptomic analysis, unbiased proteomics, and microbiome and metabolome investigations. The UCI MODEL-AD Center will leverage the resources of our NIA-funded Alzheimer’s Disease Research Center combined with AMP-AD and other human AD datasets to facilitate comparisons to the human condition to identify the best mouse models to evaluate further. All data and models will be made available without restrictions, via The Jackson Labs, and data will be explorable via the modeladexplorer.org website, and raw data freely available for download via the AD Knowledge Portal.