Influence of prenatal EGCG treatment and<i>Dyrk1a</i>dosage reduction on craniofacial features associated with Down syndrome

McElyea, Samantha Deitz; Starbuck, John M.; Tumbleson-Brink, Danika M.; Harrington, Emily; Blazek, J; Ghoneima, Ahmed; Kula, Katherine; Roper, Randall J.

doi:10.1093/hmg/ddw309

Cited by 39 publications

(65 citation statements)

References 70 publications

(117 reference statements)

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“…Treatment with pure EGCG during perinatal stages on Ts65Dn mice (25mg/kg via subcutaneous injection on PD 3–15) yielded an increase in neurogenesis and related proteins immediately after treatment cessation on PD 15, but these cellular effects were transient and were not evident at PD 45 and did not significantly improve hippocampal dependent learning and memory in trisomic mice [48]. Pregnant Ts65Dn mothers treated with 400mg/kg/day EGCG on embryonic days (E) 7 and 8 via oral gavage and saw improvements in the E9.5 1 st pharyngeal arch size and cell number and in the size and shape of the cranial vault in 6 week old mice [47]. Thus, the age at which the mice are administered an EGCG-containing therapeutic appears to be a critical factor in the efficacy of targeted therapeutics.…”

Section: Discussionmentioning

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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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: Discussionmentioning

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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“…; McElyea et al. ). This gold standard methodology is used to understand the behavioral phenotypes that are improved in Ts65Dn/Dyrk1a +/+/− mice versus Ts65Dn/Dyrk1a +/+/+ (Ts65Dn) mice, which could be specifically attributed to the extra copy of Dyrk1a on a trisomic background (Table ).…”

Section: Dissecting the Functional Role Of Dyrk1a From Humans With Pamentioning

confidence: 97%

“…; McElyea et al. ). For example, EGCG treatment at gestational (G)7‐G8 improved craniofacial precursor phenotypes in E9.5 embryos, and improved cranial vault structure in these same mice at 6 weeks of age (McElyea et al.…”

Section: An Optimal Age For Egcg Administration To Inhibit Dyrk1a Actmentioning

confidence: 97%

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Targeting trisomic treatments: optimizing Dyrk1a inhibition to improve Down syndrome deficits

Stringer

Goodlett

Roper

2017

Mol Genet Genomic Med

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Overexpression of Dual‐specificity tyrosine‐phosphorylated regulated kinase 1A (DYRK1A), located on human chromosome 21, may alter molecular processes linked to developmental deficits in Down syndrome (DS). Trisomic DYRK1A is a rational therapeutic target, and although reductions in Dyrk1a genetic dosage have shown improvements in trisomic mouse models, attempts to reduce Dyrk1a activity by pharmacological mechanisms and correct these DS‐associated phenotypes have been largely unsuccessful. Epigallocatechin‐3‐gallate (EGCG) inhibits DYRK1A activity in vitro and this action has been postulated to account for improvement of some DS‐associated phenotypes that have been reported in preclinical studies and clinical trials. However, the beneficial effects of EGCG are inconsistent and there is no direct evidence that any observed improvement actually occurs through Dyrk1a inhibition. Inconclusive outcomes likely reflect a lack of knowledge about the tissue‐specific patterns of spatial and temporal overexpression and elevated activity of Dyrk1a that may contribute to emerging DS traits during development. Emerging evidence indicates that Dyrk1a expression varies over the life span in DS mouse models, yet preclinical therapeutic treatments targeting Dyrk1a have largely not considered these developmental changes. Therapies intended to improve DS phenotypes through normalizing trisomic Dyrk1a need to optimize the timing and dose of treatment to match the spatiotemporal patterning of excessive Dyrk1a activity in relevant tissues. This will require more precise identification of developmental periods of vulnerability to enduring adverse effects of elevated Dyrk1a, representing the concurrence of increased Dyrk1a expression together with hypothesized tissue‐specific‐sensitive periods when Dyrk1a regulates cellular processes that shape the long‐term functional properties of the tissue. Future efforts targeting inhibition of trisomic Dyrk1a should identify these putative spatiotemporally specific developmental sensitive periods and determine whether normalizing Dyrk1a activity then can lead to improved outcomes in DS phenotypes.

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“…EGCG in particular improved neural crest cells (NCC)-related deficits in proliferation and migration in vitro in mandibular precursor cells from Ts65Dn E9.5 embryos. In vivo treatment with EGCG at E7 and E8, around the time of the developing NCC deficit, appeared to improve some of the NCC embryonic dysmorphology in Ts65Dn E9.5 embryos [149]. However, a longlasting EGCG treatment at a lower dose (E0-E9) did not have the same corrective effects.…”

Section: Epigallocatechin-3-gallate (Egcg)mentioning

confidence: 88%

Mitochondrial Abnormalities in Down Syndrome: Pathogenesis, Effects and Therapeutic Approaches

Izzo¹,

Mollo²,

Cicatiello³

et al. 2018

Advances in Research on Down Syndrome

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Down syndrome (DS) consists of a complex phenotype with constant features, such as mental retardation and hypotonia, and variable features, including heart defects and susceptibility to Alzheimer's disease, type 2 diabetes, obesity and immune disorders. Overexpression of genes mapping to chromosome 21 (Hsa21) is directly or indirectly responsible for pathogenesis of DS phenotypic features, as overexpressed Hsa21 genes dysregulate several other genes mapping to different chromosomes. Many of these genes are involved in mitochondrial function. Recent studies highlight a link between mitochondrial dysfunction, consistently observed in DS subjects, and DS phenotype. In this review, we first provide a basic overview of mitochondrial alterations in DS in terms of mitochondrial bioenergetics, biogenesis and morphology. We then discuss how mitochondrial malfunction may contribute to the pathogenesis of clinical manifestations and how specific Hsa21 genes may cause the disruption of mitochondrial phenotype. Finally, we focus on drugs, which affect mitochondrial function and network to propose possible therapeutic approaches aimed at improving and/or preventing various aspects of the DS phenotype. Our working hypothesis is that correcting the mitochondrial defect might improve the neurological phenotype and prevent DS-associated pathologies, thus providing a better quality of life for DS individuals and their families.

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Influence of prenatal EGCG treatment andDyrk1adosage reduction on craniofacial features associated with Down syndrome

Cited by 39 publications

References 70 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

Targeting trisomic treatments: optimizing Dyrk1a inhibition to improve Down syndrome deficits

Mitochondrial Abnormalities in Down Syndrome: Pathogenesis, Effects and Therapeutic Approaches

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