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. 2024 Apr;20(4):3080-3087.
doi: 10.1002/alz.13730. Epub 2024 Feb 11.

Gene replacement-Alzheimer's disease (GR-AD): Modeling the genetics of human dementias in mice

Kellie Benzow  1 , Kul Karanjeet  1 , Adrian L Oblak  2 , Gregory W Carter  3 , Michael Sasner  3 , Michael D Koob  1
Affiliations

Gene replacement-Alzheimer's disease (GR-AD): Modeling the genetics of human dementias in mice

Kellie Benzow et al. Alzheimers Dement. 2024 Apr.

Abstract

Introduction: Genetic studies conducted over the past four decades have provided us with a detailed catalog of genes that play critical roles in the etiology of Alzheimer's disease (AD) and related dementias (ADRDs). Despite this progress, as a field we have had only limited success in incorporating this rich complexity of human AD/ADRD genetics findings into our animal models of these diseases. Our primary goal for the gene replacement (GR)-AD project is to develop mouse lines that model the genetics of AD/ADRD as closely as possible.

Methods: To do this, we are generating mouse lines in which the genes of interest are precisely and completely replaced in the mouse genome by their full human orthologs.

Results: Each model set consists of a control line with a wild-type human allele and variant lines that precisely match the human genomic sequence in the control line except for a high-impact pathogenic mutation or risk variant.

Keywords: APOE‐GR; APP‐GR; C9ORF72‐GR; MAPT‐GR; PSEN1‐GR; PSEN2‐GR; SNCA‐GR; TARDBP‐GR; TMEM106B‐GR; TREM2‐GR; functional sequence variant; gene‐replacement mouse model; protective haplotype; risk haplotype.

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Conflict of interest statement

The authors declare no conflicts of interest. Author disclosures are available in the supporting information.

Figures

FIGURE 1
FIGURE 1
Example of the gene‐replacement (GR) approach to generating genetic models of human disease in the mouse: APOE‐GR alleles. For these lines, the mouse genomic region (30 kb) encoding the mouse Apoe gene cluster (Apoe, Apoc1, Apoc4, and Apoc2) is completely and precisely replaced by the 47‐kb syntenic region of the human genome, as shown. For these GR alleles, the transition from the mouse to the human sequence occurs within a non‐conserved region just 3′ of the mouse Tomm40 gene, and the transition from the human to mouse sequence occurs within a non‐conserved region just 3′ of the human APOC2 gene. The 47 kb of the APOE‐GR allele itself is a fully human APOE ε4 haplotype sequence. A matched line with a single nucleotide change introducing the APOE ε3 coding change has also been generated in this APOC‐GR model set.
See this image and copyright information in PMC

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