Browsing by Author "Stancombe, Kailey"

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    Effects of EGCG treatment on deficits in a radial-arm maze spatial pattern separation task in a Down syndrome mouse model
    (Office of the Vice Chancellor for Research, 2015-04-17) Stringer, Megan; Stancombe, Kailey; Gainey, Sean; Sheikh, Zahir; Abeysekera, Irushi; Goodlett, Charles R.; Roper, Randall J.
    Down syndrome (DS) is caused by three copies of human chromosome 21 (Hsa 21) and results in a constellation of phenotypes that include intellectual disability. Ts65Dn mice, the most extensively studied model of DS, have three copies of approximately half the genes on Hsa 21 and display many of the phenotypes associated with DS, including cognitive deficits. DYRK1A is found in three copies in humans with Trisomy 21 and has increased expression in a number of tissues. Dyrk1a is also found in three copies in Ts65Dn mice, and has been shown to be involved in a number of critical pathways including CNS development and osteoclastogenesis. Epigallocatechin-3-gallate (EGCG), the main polyphenol found in green tea, is an inhibitor of Dyrk1a activity. We have previously shown that a three week treatment with EGCG normalizes skeletal abnormalities in Ts65Dn mice. Previous work has found that Ts65Dn mice are significantly impaired in several hippocampal-dependent tasks, including the Morris water maze and novel object recognition. Another hippocampal-dependent process, pattern separation, is the ability to differentiate between similar memories acquired during learning. Distinctive encoding of these similar memories in hippocampal formation is thought to be necessary to distinguish between them. Experimental reductions in adult neurogenesis have produced impairments in pattern separation performance. Given that recent studies in Ts65Dn mice have reported significant reductions in adult hippocampal neurogenesis, we hypothesize that Ts65Dn mice will be impaired in the pattern separation task. Furthermore, we hypothesize that treating Ts65Dn mice with EGCG throughout task learning would improve performance to control levels. A radial arm maze-delayed non-matching-toplace pattern separation task with three different degrees of spatial separation is used. Preliminary data suggests that, in contrast to control mice, Ts65Dn mice do not improve their performance over training.
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    Epigallocatechin-3-gallate (EGCG) consumption in the Ts65Dn model of Down syndrome fails to improve behavioral deficits and is detrimental to skeletal phenotypes
    (Elsevier, 2017-08) Stringer, Megan; Abeysekera, Irushi; Thomas, Jared; LaCombe, Jonathan; Stancombe, Kailey; Stewart, Robert J.; Dria, Karl J.; Wallace, Joseph M.; Goodlett, Charles R.; Roper, Randall J.; Department of Biology, School of Science
    Down syndrome (DS) is caused by three copies of human chromosome 21 (Hsa21) and results in phenotypes including intellectual disability and skeletal deficits. Ts65Dn mice have three copies of ~ 50% of the genes homologous to Hsa21 and display phenotypes associated with DS, including cognitive deficits and skeletal abnormalities. DYRK1A is found in three copies in humans with Trisomy 21 and in Ts65Dn mice, and is involved in a number of critical pathways including neurological development and osteoclastogenesis. Epigallocatechin-3-gallate (EGCG), the main polyphenol in green tea, inhibits Dyrk1a activity. We have previously shown that EGCG treatment (~ 10 mg/kg/day) improves skeletal abnormalities in Ts65Dn mice, yet the same dose, as well as ~ 20 mg/kg/day did not rescue deficits in the Morris water maze spatial learning task (MWM), novel object recognition (NOR) or balance beam task (BB). In contrast, a recent study reported that an EGCG-containing supplement with a dose of 2–3 mg per day (~ 40–60 mg/kg/day) improved hippocampal-dependent task deficits in Ts65Dn mice. The current study investigated if an EGCG dosage similar to that study would yield similar improvements in either cognitive or skeletal deficits. Ts65Dn mice and euploid littermates were given EGCG [0.4 mg/mL] or a water control, with treatments yielding average daily intakes of ~ 50 mg/kg/day EGCG, and tested on the multivariate concentric square field (MCSF)—which assesses activity, exploratory behavior, risk assessment, risk taking, and shelter seeking—and NOR, BB, and MWM. EGCG treatment failed to improve cognitive deficits; EGCG also produced several detrimental effects on skeleton in both genotypes. In a refined HPLC-based assay, its first application in Ts65Dn mice, EGCG treatment significantly reduced kinase activity in femora but not in the cerebral cortex, cerebellum, or hippocampus. Counter to expectation, 9-week-old Ts65Dn mice exhibited a decrease in Dyrk1a protein levels in Western blot analysis in the cerebellum. The lack of beneficial therapeutic behavioral effects and potentially detrimental skeletal effects of EGCG found in Ts65Dn mice emphasize the importance of identifying dosages of EGCG that reliably improve DS phenotypes and linking those effects to actions of EGCG (or EGCG-containing supplements) in specific targets in brain and bone.
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    Epigallocatechin-3-gallate (EGCG) consumption in the Ts65Dn model of Down syndrome fails to improve behavioral deficits and is detrimental to skeletal phenotypes
    (Elsevier, 2017-08-01) Stringer, Megan; Abeysekera, Irushi; Thomas, Jared; LaCombe, Jonathan; Stancombe, Kailey; Stewart, Robert J.; Dria, Karl J.; Wallace, Joseph M.; Goodlett, Charles R.; Roper, Randall J.; Psychology, School of Science
    Down syndrome (DS) is caused by three copies of human chromosome 21 (Hsa21) and results in phenotypes including intellectual disability and skeletal deficits. Ts65Dn mice have three copies of ~50% of the genes homologous to Hsa21 and display phenotypes associated with DS, including cognitive deficits and skeletal abnormalities. DYRK1A is found in three copies in humans with Trisomy 21 and in Ts65Dn mice, and is involved in a number of critical pathways including neurological development and osteoclastogenesis. Epigallocatechin-3-gallate (EGCG), the main polyphenol in green tea, inhibits Dyrk1a activity. We have previously shown that EGCG treatment (~10mg/kg/day) improves skeletal abnormalities in Ts65Dn mice, yet the same dose, as well as ~20mg/kg/day did not rescue deficits in the Morris water maze spatial learning task (MWM), novel object recognition (NOR) or balance beam task (BB). In contrast, a recent study reported that an EGCG-containing supplement with a dose of 2-3mg per day (~40-60mg/kg/day) improved hippocampal-dependent task deficits in Ts65Dn mice. The current study investigated if an EGCG dosage similar to that study would yield similar improvements in either cognitive or skeletal deficits. Ts65Dn mice and euploid littermates were given EGCG [0.4mg/mL] or a water control, with treatments yielding average daily intakes of ~50mg/kg/day EGCG, and tested on the multivariate concentric square field (MCSF)-which assesses activity, exploratory behavior, risk assessment, risk taking, and shelter seeking-and NOR, BB, and MWM. EGCG treatment failed to improve cognitive deficits; EGCG also produced several detrimental effects on skeleton in both genotypes. In a refined HPLC-based assay, its first application in Ts65Dn mice, EGCG treatment significantly reduced kinase activity in femora but not in the cerebral cortex, cerebellum, or hippocampus. Counter to expectation, 9-week-old Ts65Dn mice exhibited a decrease in Dyrk1a protein levels in Western blot analysis in the cerebellum. The lack of beneficial therapeutic behavioral effects and potentially detrimental skeletal effects of EGCG found in Ts65Dn mice emphasize the importance of identifying dosages of EGCG that reliably improve DS phenotypes and linking those effects to actions of EGCG (or EGCG-containing supplements) in specific targets in brain and bone.