Full human gene replacement mouse models of Alzheimer's Disease

This application is proposing to continue and expand the collaboration between the Koob lab at the University of Minnesota and the MODEL-AD Center. We have developed Gene Replacement (GR) approaches that allow us to replace mouse genes with their full human orthologue alleles. The GR targets for this project include many of the human genes most central to the etiology of AD, including APP, PSEN1, PSEN2, and MAPT, as well as genes that play pivotal roles in modulating AD risk, including the APOE gene cluster, the TREM2 gene cluster, the critical region of the MS4A gene cluster, and INPP5D. A set of models will be generated for each GR target genomic region, consisting of a control line with a wt human genomic sequence, and at least one matching line with either a pathogenic mutation or risk variant in that same human genomic sequence. Basic QC evaluations of each GR allele will be performed at the University of Minnesota, and MODEL-AD will then validate them by confirming that each variant line exhibits the expected AD-related endophenotypes. The human alleles that pass the QC and endophenotype validations will then be incorporated into base AD models with additional AD alleles, with the ultimate goal of recreating the human genetics and pathophysiology of AD as closely as is possible in a mouse. JAX will distribute all mouse lines generated by this project without restrictions.