Species: Mouse
Genes: MAPT, MAPT-AS1, Mapt
Modification: MAPT: Knock-In; MAPT-AS1: Knock-In; Mapt: Knock-Out
Disease Relevance: Alzheimer's Disease, Frontotemporal Dementia, Other Tauopathy
Strain Name: B6J.B6N-Tc(HSA17)1Mdk/J
Genetic Background: C57BL/6J
Availability: Available from The Jackson Laboratory, Stock No. 033668.

Summary

MAPT(H2.1)-GR mice are among a series of models developed by Michael Koob and colleagues at the University of Minnesota, collectively referred to as Gene Replacement – Alzheimer’s Disease (GR-AD) mice. In GR-AD mice, “genes of interest are precisely and completely replaced in the mouse genome by their full human orthologs, along with all known overlapping, co-regulated non-coding RNAs (Benzow et al., 2024).”

In MAPT(H2.1)-GR mice, a 190-kb region from human chromosome 17—encompassing the entire human MAPT gene—replaces the corresponding Mapt-containing region on mouse chromosome 11. MAPT(H2.1)-GR mice carry the MAPT H2 haplotype. Mice carrying the wild-type H1 haplotype or H1 with the pathogenic N279K, P301L, or 10IVS+16 C>T mutations are also available (see Related Strains below). These transchromosomic lines are unique among mouse models—in addition to the entire MAPT gene, they carry MAPT-AS1, a natural antisense transcript that regulates MAPT translation (Simone et al., 2021; see May 2021 news).

MAPT(H2.1)-GR mice generate all six tau protein isoforms, and MAPT-AS1 transcripts are expressed. Homozygous mice are viable and fertile.

Further characterization of MAPT(H2.1)-GR and other GR-AD lines will be conducted as part of the MODEL-AD project. The Jackson Laboratory is distributing GR-AD mice for academic and commercial use without restrictions.

Modification Details

A 190-kb region from human chromosome 17—including MAPT (H2 haplotype), MAPT-AS1, and the SPPL2C sequence, which is contained within MAPT-AS1—replaced a 157-kb region on mouse chromosome 11 between, but not including, Crhr1 and Kansl1.

Related Strains

MAPT(H1.0)-GR. These transchromosomic mice carry human MAPT (wild-type H1 haplotype) and MAPT-AS1 knocked into the mouse Mapt locus. They generate all six tau protein isoforms. MAPT-AS1 transcripts are expressed. MAPT(H1.0)-GR mice are available from The Jackson Laboratory, Stock No. 035398.

MAPT(H1.0*N279K)-GR. These transchromosomic mice carry human MAPT (H1 haplotype) with the N279K mutation and MAPT-AS1 knocked into the mouse Mapt locus. They generate all six tau protein isoforms. MAPT-AS1 transcripts are expressed. MAPT(H1.0*N279K)-GR mice are available from The Jackson Laboratory, Stock No. 035794.

MAPT(H1.0*)P301L-GR. These transchromosomic mice carry human MAPT (H1 haplotype) with the P301L mutation and MAPT-AS1 knocked into the mouse Mapt locus. They generate all six tau protein isoforms. MAPT-AS1 transcripts are expressed. MAPT(H1.0*)P301L-GR mice are available from The Jackson Laboratory, Stock No. 037420.

MAPT 10IVS+16 C>T. These transchromosomic mice carry human MAPT (H1 haplotype with a noncoding mutation in intron 10) and MAPT-AS1 knocked into the mouse Mapt locus. MAPT 10IVS+16 C>T mice are available from The Jackson Laboratory, Stock No. 036664.

Phenotype Characterization

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References

Mutations Citations

1. MAPT N279K
2. MAPT P301L
3. MAPT IVS10+16 C>T

News Citations

1. MIR-NATs: Noncoding RNAs That Rein in Aggregating Proteins? 22 May 2021

Research Models Citations

1. MAPT(H1.0)-GR
2. MAPT(H1.0*N279K)-GR
3. MAPT(H1.0*)P301L-GR
4. MAPT 10IVS+16 C>T

Paper Citations

1. Benzow K, Karanjeet K, Oblak AL, Carter GW, Sasner M, Koob MD. Gene replacement-Alzheimer's disease (GR-AD): Modeling the genetics of human dementias in mice. Alzheimers Dement. 2024 Apr;20(4):3080-3087. Epub 2024 Feb 11 PubMed.
2. Simone R, Javad F, Emmett W, Wilkins OG, Almeida FL, Barahona-Torres N, Zareba-Paslawska J, Ehteramyan M, Zuccotti P, Modelska A, Siva K, Virdi GS, Mitchell JS, Harley J, Kay VA, Hondhamuni G, Trabzuni D, Ryten M, Wray S, Preza E, Kia DA, Pittman A, Ferrari R, Manzoni C, Lees A, Hardy JA, Denti MA, Quattrone A, Patani R, Svenningsson P, Warner TT, Plagnol V, Ule J, de Silva R. MIR-NATs repress MAPT translation and aid proteostasis in neurodegeneration. Nature. 2021 Jun;594(7861):117-123. Epub 2021 May 19 PubMed.

External Citations

1. MODEL-AD
2. The Jackson Laboratory, Stock No. 035398
3. The Jackson Laboratory, Stock No. 035794
4. The Jackson Laboratory, Stock No. 037420
5. The Jackson Laboratory, Stock No. 036664
6. The Jackson Laboratory, Stock No. 033668

Further Reading