Species: Mouse
Modification: Multi-transgene
Disease Relevance: Down's Syndrome, Alzheimer's Disease
Strain Name: B6EiC3Sn a/A-Ts(17¹⁶)65Dn/J
Genetic Background: B6/C3H
Availability: Available from The Jackson Lab: Stock# 001924. Also available as a strain without blindness from The Jackson Lab Stock# 005252.

Summary

Ts(17¹⁶)65Dn mice (Ts65Dn) have been extensively studied as a Down syndrome mouse model. The Ts65Dn line was isolated after X-ray irradiation, carrying a segment with approximately 100 genes homologous to human chromosome 21 (Hsa21) (Davisson et al., 1990, Reeves et al., 1995). The mice are aneuploid and carry the translocation chromosome, Mmu1716 (17¹⁶), as a freely segregating, supernumerary chromosome that includes approximately 13.4 Mb of distal chromosome 16 fused with about 10 Mb of chromosome 17, just proximal to the centromere. The centromeric region of Mmu17 carries around 30 protein coding genes that are not homologous with chromosome 21 (Duchon et al., 2011).

Ts65Dn mice exhibit segmental trisomy on a segment of mouse chromosome 16, encompassing a region syntenic to Hsa21 and housing the murine App gene. These mice display elevated levels of full-length murine App and its derivatives, including Aβ40 and Aβ42 (Hunter et al., 2004b). They showed neuropathological changes and age-related behavioral alterations akin to DS-AD (Belichenko et al., 2015). Moreover, Ts65Dn mice show increased Tau expression, likely due to an additional copy of Dyrk1A, which acts as one of the tau kinases, augmenting tau mRNA stability and mediating tau phosphorylation (Liu et al., 2008; Qian et al., 2013).

Neuropathology

Neuropathological changes linked to aging are marked by an increase in amyloid precursor protein (APP) and soluble amyloid-beta (Aβ) in in the cortex and hippocampus, though notably without the formation of Aβ plaques, as reported in several studies (Ahmed et al., 2017; Choi et al., 2009; Holtzman et al., 1996; Hunter et al., 2003; Illouz et al., 2019b; Reeves et al., 1995; Tallino et al., 2022). Also, an increase in soluble Aβ oligomers and small amyloidal extracellular inclusions in the deep granular cell layer of the cerebellum has been reported. By 12 months of age, early biochemical alterations are evident, including the appearance of hippocampal Aβ oligomers (Sansevero et al., 2016).

These Aβ-associated changes coincide with significant tau modifications, such as alterations in 3R/4R splicing that stabilize tau mRNA (Qian et al., 2013) and increased tau phosphorylation (Garcia-Cerro et al., 2017; Liu et al., 2008; Yin et al., 2017). However, these mice do not develop neurofibrillary tangles. 

In Down syndrome (DS), an extra copy of the dual-specificity tyrosine-phosphorylated and regulated kinase 1A (Dyrk1A) gene due to trisomy 21 results in Dyrk1A overexpression and heightened kinase activity in the brain. In the Ts65Dn mouse model of DS, elevated Dyrk1A expression and activity at 15 months lead to increased tau phosphorylation (Liu et al., 2008). Yin and colleagues further confirmed that this gene overdosage drives Dyrk1A overexpression in Ts65Dn mice at all ages studied, from postnatal day 5 (P5) to P35, promoting dysregulation of tau exon 10, enhancing 3R-tau expression, and reducing 4R-tau expression (Yin et al., 2017). These findings highlight how Dyrk1A overexpression affects tau isoform regulation and phosphorylation, contributing to age-associated neuropathological changes in DS.

Alongside Aβ and tau pathology, signs of cholinergic neurodegeneration emerge between 6 and 12 months, particularly within the basal forebrain, characterized by a reduction in nerve growth factor (NGF), which correlates with impaired synaptic plasticity and reduced adult hippocampal neurogenesis (Corrales et al., 2013; Dierssen et al., 1997; Granholm et al., 2000; Salehi et al., 2006; Seo and Isacson, 2005). The convergence of these biochemical and neurodegenerative changes underscores the early vulnerability of hippocampal and basal forebrain circuits in aging. Moreover, by 14 months of age, the progressive loss of cholinergic neurons in Ts65Dn mice becomes evident, with significantly fewer neurons compared to younger trisomic mice, further emphasizing the age-related nature of these neuropathological changes (Kirstein et al., 2022). Compounding these processes, the ongoing degeneration of norepinephrine neurons in the locus coeruleus leads to impaired norepinephrine signaling (Hamlett et al., 2020b; Lockrow et al., 2011; Salehi et al., 2009), contributing to broader cognitive and functional deficits with advancing age.

Inflammation plays a substantial role in aging, illustrated by elevated cyclooxygenase-2 (COX2) and prostaglandin E2 (PGE2) levels in both microglia and neurons by 8 months of age (Pinto et al., 2020), which are coupled with age-related microglial morphological changes (Hamlett et al., 2020a). Additionally, by 10 to 18 months, an elevated density of CD45+ microglia cells are found in the hippocampus and basal forebrain (Hamlett et al., 2020a; Hunter et al., 2004a; Lockrow et al., 2012), with IBA1 upregulation at 12 months (Rueda et al., 2018) and reduced expression of the homeostatic microglial marker P2RY12 at 15 months (Illouz et al., 2019b). Structural abnormalities in the hippocampus also begin to appear by 16-17 months, including a reduction in granule cells in the dentate gyrus and an increase in pyramidal cells within the CA3 subfield (Lorenzi and Reeves, 2006; Ayberk Kurt et al., 2004). Despite these findings, phenotypic drift of unclear origin has been observed, and recent studies failed to replicate earlier findings (Lorenzi and Reeves, 2006; Klein and Haydar, 2022).

A hallmark of aging is the persistent decline in actively proliferating cells within the germinal zone of the dorsal telencephalon, a trend that continues postnatally and results in fewer proliferating cells in the hippocampus, further highlighting impaired neurogenesis (Klein and Haydar, 2022).

Furthermore, age-related declines in mitochondrial bioenergetics (Lanzillotta et al., 2021) contribute to broader brain dysfunction (Valenti et al., 2021). The oxidative stress response, which intensifies around 6 months of age, leads to significant accumulation of oxidative damage to proteins, arising from elevated oxidative stress and decreased activity of degradative systems, such as autophagy (Tramutola et al., 2016). Additionally, aging-related insulin resistance in the brain, observable as early as 1 month and progressing with age, is marked by impaired insulin signaling, further contributing to neurodegenerative vulnerability in Ts65Dn mice (Lanzillotta et al., 2021). Together, these processes underscore the compounding nature of neuropathological and biochemical changes associated with aging.

Behavioral/Neurological phenotypes

The neuropathological changes in this mouse model are accompanied by a range of behavioral and neurological phenotypes, including deficits in spatial learning and memory, as well as developmental delays in sensorimotor milestones. These are often coupled with locomotor hyperactivity, lack of behavioral inhibition, and stereotypic behaviors (Davisson et al., 1990; Costa et al., 1999). Additionally, these mice display a higher anxiety threshold and elevated traveling speed. They also show motor deficits in swimming tasks reflected in reduced usage of highly spatial strategies and decreased spatial accuracy (Illouz et al., 2019a).

Delayed motor skill acquisition, impaired coordination, hyperactivity, and reduced attention are also common, with notable impairments in hippocampal-dependent functions such as contextual fear conditioning, working memory, and long-term spatial memory.

Ts65Dn mice demonstrate impaired hippocampal long-term potentiation (LTP) due to excessive GABA-mediated inhibition (Klein and Haydar, 2022). Additionally, in newborn Ts65Dn mice, an increased number of inhibitory neurons is observed in the forebrain, along with heightened spontaneous inhibitory postsynaptic currents in the pyramidal neurons of the hippocampal CA1 region (Rueda et al., 2020). These alterations highlight early disruptions in excitatory-inhibitory balance, which are thought to underlie the cognitive impairments seen in this model of Down syndrome.

Ts65Dn mice exhibit several synaptic and neuronal alterations. These include an increased synaptic cleft, more inhibitory synapses, and fewer excitatory synapses, alongside an elevated number of GABAergic neurons (Illouz et al., 2019a). Additionally, there is decreased synaptic density in both the hippocampus and neocortex (Klein and Haydar, 2022), accompanied by enlarged pre-synaptic boutons and spines. Changes in the physical distribution of afferent inputs are also noted when compared to euploid controls (Klein and Haydar, 2022), contributing to the altered synaptic and circuit dynamics in this model.

Cognitive and motor deficits are exacerbated by behavioral impairments linked to inhibition of the locus coeruleus, a key structure involved in attention and arousal. This inhibition correlates with an upregulation of β1- and β2-adrenoreceptors, along with increased CD45 expression in microglia, reflecting an underlying neuroinflammatory response (Hamlett et al., 2020b). The combination of cognitive decline, motor dysfunction, and heightened neuroinflammation creates a complex behavioral and neurological profile that mirrors the progressive nature of these neuropathological alterations.

Thus, these behavioral alterations generally emerge around 6 to 12 months of age, a period that correlates with the onset of significant neuropathological changes in mouse models like Ts65Dn. Some developmental and hyperactivity-related symptoms can be seen earlier, during juvenile stages.

Developmental phenotypes

Neurological alterations in Ts65Dn mice are marked by significant changes in the distribution and density of key interneurons, such as somatostatin, calretinin, and parvalbumin-expressing cells, accompanied by an overall increase in inhibitory synapses throughout the cortex (Klein and Haydar, 2022). The changes in interneurons, such as somatostatin and parvalbumin distribution, and the increase in inhibitory synapses throughout the cortex, have been observed between postnatal days 8 to 30. These synaptic changes are further exacerbated by structural deficits in myelination, specifically characterized by thinner myelin sheaths. This myelin deficit is likely the result of impaired maturation of oligodendrocyte precursor cells, along with decreased levels of myelin-associated glycoprotein and myelin basic protein in the corpus callosum (Klein and Haydar, 2022; Aziz et al., 2018).

In parallel, a significant reduction in the number of excitatory neurons, as indicated by T-box brain 1 (TBR1) staining, has been observed in the cortex of Ts65Dn mice (Aziz et al., 2018). These alterations in both neuronal and glial populations reflect broader impacts on brain development, including deficits in somatic growth, neurogenesis, and overall brain morphogenesis (Aziz et al., 2018). Collectively, these neurological changes contribute to the complex neurodevelopmental phenotype seen in Ts65Dn mice, highlighting the interplay between altered synaptic dynamics, disrupted myelination, and reduced excitatory neuronal populations.

Moreover, Ts65Dn mice show a developmental shift from neuronal to astrocytic lineage, leading to an increased percentage of astroglial cells in the hippocampus (Klein and Haydar, 2022). This astrocytic increase is also evident in both the cortex and hippocampus (Holtzman et al., 1996; Klein and Haydar, 2022).

Of note, Ts65Dn mice are on a genetic background that leads to blindness in about 25 percent of progeny due to the retinal degeneration allele Pde6b^rd1. Mice that are homozygous for the rd1 allele are affected. An alternative strain is available (The Jackson Lab Stock# 005252) with a virtually identical genetic background except that it is wild-type for Pde6b^rd1. Only subtle phenotypic differences have been observed between the two strains (Costa et al., 2010).

Other phenotypes

Ts65Dn mice exhibit a range of physical and physiological abnormalities, including reduced birthweight, muscular trembling, male sterility, and distinctive facial features (Reeves et al., 1995). In the Jax substrain 001924, the segregating Pde6brd1 allele causes retinal degeneration and blindness, with substrain 005252 as an alternative (Tielemans et al., 2023). These mice also display altered lung density, reduced lung capacities, and increased susceptibility to pulmonary vascular diseases (Tielemans et al., 2023). Neurologically, at 5 months, they show altered ultrasonic vocalizations (Glass et al., 2023), while adults present dysphagia symptoms, such as slower swallow rates and longer inter-swallow intervals (Glass et al., 2019).

Additionally, Ts65Dn mice demonstrate reduced blood pressure and congenital heart defects like right aortic arch and septal anomalies (Moore, 2006; DeRuisseau et al., 2019). Skeletal issues and peripheral immune changes, including decreased B- and T-cell counts, are present (Tielemans et al., 2023). By 12 months, elevated hippocampal proinflammatory cytokines (Ahmed et al., 2017; Rueda et al., 2018) and serum proinflammatory markers (Hamlett et al., 2020a) are evident, along with increased blood levels of Aβ40 and Aβ42 (Illouz et al., 2017). Together, these features highlight the broad pathological profile of this model.

Modification details

Cesium irradiation produced a reciprocal translocation of chromosomes 16 and 17, creating a freely segregating, supernumerary chromosome Mmu17¹⁶ (1716) (Reeves et al., 1995). The 17¹⁶ chromosome carries approximately 13.4 Mb of distal chromosome 16, from Mrpl39 to Zfp295, fused with about 10 Mb of chromosome 17, just proximal to the centromere. The precise locations of the chromosome 16 and chromosome 17 breakpoints are 84,351,351 bp and 9,426,822 bp (NCBI m37/mm9), respectively (Reinholdt et al., 2011).

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:

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.

TcMAC21. This mouse model contains a nearly complete and freely segregating long arm of Hsa21 (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. 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. 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.

Phenotype Characterization

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References

Research Models Citations

1. Dp1Tyb
2. Dp9Tyb
3. Dp(16)1Yey/+
4. TcMAC21

Paper Citations

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External Citations

1. Jackson Lab Stock# 005252
2. Jax substrain 001924
3. substrain 005252
4. Stock# 001924
5. Stock# 005252

Further Reading

No Available Further Reading