Low dose EGCG treatment beginning in adolescence does not improve cognitive impairment in a Down syndrome mouse model

Stringer, Megan; Abeysekera, Irushi; Dria, Karl J.; Roper, Randall J.; Goodlett, Charles R.

doi:10.1016/j.pbb.2015.09.002

Cited by 37 publications

(56 citation statements)

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“…We and others have shown that Ts65Dn mice exhibit behavioral and functional neurological deficits, including a variety of deficits on learning and memory tasks [20, 21]. Ts65Dn mice show deficits in novel object recognition (NOR) and spontaneous alternation [6], show increased locomotor activity [22, 23], have deficits in the Morris water maze (MWM) place learning (using the hidden platform version) and (under some testing conditions) on the cued task of the visible platform version [20, 23, 24], have gait abnormalities [25] and motor coordination deficits [23]. For skeletal parameters in DS mouse models, we and others have identified significant deficits in BMD, trabecular bone parameters (thickness, separation and number) and cortical bone measures in Ts65Dn mice compared to euploid control mice [17].…”

Section: Introductionmentioning

confidence: 99%

“…These studies support the growing possibility that Dyrk1a overexpression is both spatially and temporally regulated during development in DS. Furthermore, only a few studies have reported levels of Dyrk1a kinase activity; 15-month-old Ts65Dn mice exhibited increased Dyrk1a kinase activity in brain tissue as compared to controls [35], whereas another study reported no differences in Dyrk1a kinase activity in cerebellum hippocampus and cerebral cortex between 6 week old Ts65Dn and control mice [23]. Understanding functional Dyrk1a kinase activity differences between Ts65Dn and control mice at specific developmental periods in specific tissues is a necessary component for assessing the efficacy of pharmacotherapies targeting Dyrk1a.…”

Section: Introductionmentioning

confidence: 99%

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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

Stringer

Abeysekera

Thomas

et al. 2017

Physiology & Behavior

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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 2–3 mg 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 [0.4 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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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Epigallocatechin-3-gallate (EGCG) consumption in the Ts65Dn model of Down syndrome fails to improve behavioral deficits and is detrimental to skeletal phenotypes

Stringer

Abeysekera

Thomas

et al. 2017

Physiology & Behavior

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“…20 It is important to note that the only study that examined DYRK1A activity in the Ts65Dn mouse showed marginal differences in comparison with euploid mice and marginal effects of EGCG on its activity. 18 However, due to the relatively small sample size in conjunction with the intrinsic phenotypic variability of Ts65Dn mice, further observations are required to confirm this finding. In addition, protein expression, including that of DYRK1A, may change across brain regions and ages.…”

Section: Potential Usefulness Of Egcg Treatment Of Down Syndromementioning

confidence: 98%

“…17 This study examined the effects of green tea extracts containing EGCG on learning and memory in Ts65Dn and in TgDyrk1A mice. Adult TgDyrk1A and Ts65Dn mice (3 months of age) that were treated for one month with green tea extracts containing EGCG exhibited a memory improvement, assessed using the Morris Water Maze and Novel Object Recognition tests 17 A subsequent study by Stringer et al 18 tested the effects of pure EGCG (20 mg/kg/day) in Ts65Dn mice starting from weaning, for either three weeks (i.e. until adolescence) or seven weeks (i.e., until adulthood).…”

Section: Effects Of Egcg In the Ts65dn Model Of Down Syndromementioning

confidence: 99%

“…The available data in Ts65Dn mice show that treatment with EGCG may 17 or may not 18,19 have a positive effect on behavior, and that it restores hippocampal development, but has no long-term impact on hippocampal neuroanatomy and behavior. 20 It is important to note that the only study that examined DYRK1A activity in the Ts65Dn mouse showed marginal differences in comparison with euploid mice and marginal effects of EGCG on its activity.…”

Section: Potential Usefulness Of Egcg Treatment Of Down Syndromementioning

confidence: 99%

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Epigallocatechin gallate: A useful therapy for cognitive disability in Down syndrome?

et al. 2017

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Behavioral Phenotyping for Down Syndrome in Mice

et al. 2020

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Down syndrome (DS) is the most frequent genetic cause of intellectual disability, characterized by alterations in different behavioral symptom domains: neurodevelopment, motor behavior, and cognition. As mouse models have the potential to generate data regarding the neurological basis for the specific behavioral profile of DS, and may indicate pharmacological treatments with the potential to affect their behavioral phenotype, it is important to be able to assess disease‐relevant behavioral traits in animal models in order to provide biological plausibility to the potential findings. The field is at a juncture that requires assessments that may effectively translate the findings acquired in mouse models to humans with DS. In this article, behavioral tests are described that are relevant to the domains affected in DS. A neurodevelopmental behavioral screen, the balance beam test, and the Multivariate Concentric Square Field test to assess multiple behavioral phenotypes and locomotion are described, discussing the ways to merge these findings to more fully understand cognitive strengths and weaknesses in this population. New directions for approaches to cognitive assessment in mice and humans are discussed. © 2020 Wiley Periodicals LLC. Basic Protocol 1: Preweaning neurodevelopmental battery Basic Protocol 2: Balance beam Basic Protocol 3: Multivariate concentric square field test (MCSF)

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Low dose EGCG treatment beginning in adolescence does not improve cognitive impairment in a Down syndrome mouse model

Cited by 37 publications

References 55 publications

Epigallocatechin-3-gallate (EGCG) consumption in the Ts65Dn model of Down syndrome fails to improve behavioral deficits and is detrimental to skeletal phenotypes

Epigallocatechin-3-gallate (EGCG) consumption in the Ts65Dn model of Down syndrome fails to improve behavioral deficits and is detrimental to skeletal phenotypes

Epigallocatechin gallate: A useful therapy for cognitive disability in Down syndrome?

Behavioral Phenotyping for Down Syndrome in Mice

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