Species: Mouse
Modification: Multi-transgene
Disease Relevance: Down's Syndrome, Alzheimer's Disease
Strain Name: TcMAC21
Genetic Background: B6/D2 (C57BL/6J (B6) x DBA/2J (D2))
Availability: Available from Riken Animal Resource RBRC05796. Also available from The Jackson Laboratory #035561.

TcMAC21 is a Down syndrome mouse model which contains a nearly complete and freely segregating long arm of human chromosome 21 (including the APP gene) in the form of a hybrid mouse artificial chromosome, with no detectable mosaicism in a broad spectrum of tissues and cell types (Kazuki et al., 2020). TcMAC21 recapitulates many Down syndrome phenotypes including deficits in learning, memory and synaptic plasticity, anomalies in heart, craniofacial skeleton and brain development, and molecular/cellular alterations. 

Neuropathology
Elevated levels of APP and its cleavage products, Aβ40 and Aβ42, have been observed in the TcMAC21 model at 15–24 months of age, but amyloid plaque pathology has not been detected (Kazuki et al., 2020). The model exhibits dysmorphology of the brain with cerebellar hypoplasia—enlarged lateral ventricles and superior colliculus, and smaller cerebellum.

Behavioral/Neurological Phenotypes
At 3-4 months of age, at the single age tested, the model recapitulated Down syndrome-associated deficits in learning and memory as assessed by the Morris water maze and open field test (Kazuki et al., 2020). Long-term potentiation was also affected. No differences were detected in nesting abilities compared to controls.

The model also shows larger evoked excitatory postsynaptic currents (EPSCs) without changes to inhibitory postsynaptic currents (IPSCs), resulting in an increased excitation-inhibition ratio (Shao et al., 2023).

Other Phenotypes
The model exhibits a reduced body size and weight, retrusion of the midface skeleton and mandible, congenital heart defects of septation and outflow tract, hematological abnormalities including increased platelet count, increased splenomegaly and white pulp hypertrophy, and reduced frequency of granulocytes/macrophages (Kazuki et al., 2020). The mice also exhibit hypermetabolism and raised body temperature (Sarver et al., 2023). They are hyperactive and remain consistently lean even after a high-fat diet challenge, and have altered glucose and insulin biology.

Modification Details
TcMAC21 has a freely and stably-segregating hybrid mouse artificial chromosome (MAC) that contains a nearly complete long-arm of human chromosome 21 (Hsa21q; 34 MB including ~93 percent of protein-coding genes and ~79 percent of non-coding sequences; Kazuki et al., 2020).

This summary was prepared by the Trisomy 21 Research Society.

Related Models

The following are additional Down syndrome models carrying either a Cre/lox-generated partial duplication of mouse chromosome 16 (the ortholog of human chromosome 21, Hsa21), a hybrid chromosome containing segments of mouse chromosomes 16 and 17 generated by irradiation, or the long arm of Hsa21 in a mouse artificial chromosome:

Ts65Dn. These mice have been extensively studied as a Down syndrome mouse model. The line is aneuploid carrying a freely segregating, supernumerary chromosome generated by irradiation. The extra chromosome harbors a piece of mouse chromosome 16, including App, fused with a piece of mouse chromosome 17. These mice display elevated levels of full-length murine App and its derivatives, including Aβ40 and Aβ42, but no plaque pathology. Moreover, Ts65Dn mice show increased tau expression and altered 3R/4R tau mRNA splicing. They also have multiple neuropathological changes and age-related behavioral alterations akin to Down syndrome AD. Ts65Dn mice also exhibit a range of peripheral physical and physiological DS-like deficits.

Dp1Tyb. These mice have an extra copy of approximately 65 percent of the mouse genes on chromosome 16, including App, generated by Cre/lox engineering. They have neurodevelopmental alterations resulting in reduced medial prefrontal cortex and dorsal hippocampus volumes, reduced density of neurons, and increased density of microglia in the hippocampus. Spatial working memory, exploratory behavior, and fear memory are impaired, as well as motor function and sleep architecture. Heart, lung, hematologic, skeletal, ear, and metabolic abnormalities similar to those associated with Down syndrome have been reported.

Dp9Tyb. These mice carry a duplication of mouse chromosome 16 generated by Cre/lox engineering that spans a segment between the Lipi and Hunk genes, including App. The duplication lacks some genes suspected to be relevant to Down syndrome-associated AD, such as Dyrk1a and Bace2. Dp9Tyb mice have not yet been well characterized.

Dp(16)1Yey/+. This mouse model has an extra copy of approximately 65 percent of the mouse genes on chromosome 16 that are orthologous to Hsa21 generated by Cre/lox engineering. It is characterized by neuronal loss in the entorhinal cortex, locus coeruleus, and the basal forebrain magnocellular complex; increased tau pathology and increased astrocyte and microglia levels. Impairments in contextual memory, spatial learning, novel object recognition memory, and vocalizations. Altered motor coordination, sleep patterns, hearing, and vocalizations. Also, cardiopulmonary, craniofacial, skeletal, reproductive, immunological, and metabolic anomalies.

Phenotype Characterization

Q&A with Model Creator

Q&A with expert Randall Roper

What would you say are the unique advantages of this model? 
The model contains a nearly complete and freely segregating Hsa21q as a mouse artificial chromosome with no detectable mosaicism.

What do you think this model is best used for? 
Down syndrome-related research.

What caveats are associated with this model? 
TcMAC21 females are fertile, males are infertile. This model has had problems with reproduction and availability from commercial sources

Anything else useful or particular about this model you think our readers would like to know? 
Litter size ranging from 2 to 9 with an average of 6 pups, and 48 percent of offspring are TcMAC21.

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References

Research Models Citations

1. Ts65Dn
2. Dp1Tyb
3. Dp9Tyb
4. Dp(16)1Yey/+

Paper Citations

1. Kazuki Y, Gao FJ, Li Y, Moyer AJ, Devenney B, Hiramatsu K, Miyagawa-Tomita S, Abe S, Kazuki K, Kajitani N, Uno N, Takehara S, Takiguchi M, Yamakawa M, Hasegawa A, Shimizu R, Matsukura S, Noda N, Ogonuki N, Inoue K, Matoba S, Ogura A, Florea LD, Savonenko A, Xiao M, Wu D, Batista DA, Yang J, Qiu Z, Singh N, Richtsmeier JT, Takeuchi T, Oshimura M, Reeves RH. A non-mosaic transchromosomic mouse model of down syndrome carrying the long arm of human chromosome 21. Elife. 2020 Jun 29;9 PubMed.
2. Shao LR, Gao F, Chinnasamy V, Kazuki Y, Oshimura M, Reeves RH, Stafstrom CE. Increased propensity for infantile spasms and altered neocortical excitation-inhibition balance in a mouse model of down syndrome carrying human chromosome 21. Neurobiol Dis. 2023 Aug;184:106198. Epub 2023 Jun 13 PubMed.
3. Sarver DC, Xu C, Rodriguez S, Aja S, Jaffe AE, Gao FJ, Delannoy M, Periasamy M, Kazuki Y, Oshimura M, Reeves RH, Wong GW. Hypermetabolism in mice carrying a near-complete human chromosome 21. Elife. 2023 May 30;12 PubMed.

Other Citations

1. Randall Roper

External Citations

1. Riken Animal Resource RBRC05796
2. The Jackson Laboratory #035561

Further Reading

No Available Further Reading