# Full human gene replacement mouse models of Alzheimer's Disease

> **NIH NIH RF1** · UNIVERSITY OF MINNESOTA · 2022 · $4,147,326

## Abstract

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.

## Key facts

- **NIH application ID:** 10525102
- **Project number:** 1RF1AG079125-01
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** MICHAEL D KOOB
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $4,147,326
- **Award type:** 1
- **Project period:** 2022-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10525102

## Citation

> US National Institutes of Health, RePORTER application 10525102, Full human gene replacement mouse models of Alzheimer's Disease (1RF1AG079125-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10525102. Licensed CC0.

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