Molecular Rescue of Dyrk1A Overexpression Alterations in Mice with Fontup® Dietary Supplement: Role of Green Tea Catechins

Gu, Yuchen; Moroy, Gautier; Paul, Jean–Louis; Rebillat, Anne-Sophie; Dierssen, Mara; Torre, Rafael de la; Cieuta‐Walti, Cécile; Dairou, Julien; Janel, Nathalie

doi:10.3390/ijms21041404

Cited by 17 publications

(27 citation statements)

References 53 publications

(81 reference statements)

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“…EGCG exerts broad effects on several nonneuronal targets, including myelination (57) and microbiota (58). Several studies have demonstrated that EGCG crosses the blood-brain barrier in rodents after oral administration (59)(60)(61), including in TgDyrk1A transgenic mice, another genetic model of Down syndrome (62). In fact, EGCG has been detected in rat frontal cortex and hippocampus (60), so the effects observed in our study could be, indeed, mediated by direct action of EGCG on these structures.…”

Section: Discussionsupporting

confidence: 56%

Prefrontal–hippocampal functional connectivity encodes recognition memory and is impaired in intellectual disability

Alemany-González

Gener

Nebot

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Down syndrome (DS) is the most common form of intellectual disability. The cognitive alterations in DS are thought to depend on brain regions critical for learning and memory such as the prefrontal cortex (PFC) and the hippocampus (HPC). Neuroimaging studies suggest that increased brain connectivity correlates with lower intelligence quotients (IQ) in individuals with DS; however, its contribution to cognitive impairment is unresolved. We recorded neural activity in the PFC and HPC of the trisomic Ts65Dn mouse model of DS during quiet wakefulness, natural sleep, and the performance of a memory test. During rest, trisomic mice showed increased theta oscillations and cross-frequency coupling in the PFC and HPC while prefrontal–hippocampal synchronization was strengthened, suggesting hypersynchronous local and cross-regional processing. During sleep, slow waves were reduced, and gamma oscillations amplified in Ts65Dn mice, likely reflecting prolonged light sleep. Moreover, hippocampal sharp-wave ripples were disrupted, which may have further contributed to deficient memory consolidation. Memory performance in euploid mice correlated strongly with functional connectivity measures that indicated a hippocampal control over memory acquisition and retrieval at theta and gamma frequencies, respectively. By contrast, trisomic mice exhibited poor memory abilities and disordered prefrontal–hippocampal functional connectivity. Memory performance and key neurophysiological alterations were rescued after 1 month of chronic administration of a green tea extract containing epigallocatequin-3-gallate (EGCG), which improves executive function in young adults with DS and Ts65Dn mice. Our findings suggest that abnormal prefrontal–hippocampal circuit dynamics are candidate neural mechanisms for memory impairment in DS.

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Section: Discussionsupporting

confidence: 56%

Prefrontal–hippocampal functional connectivity encodes recognition memory and is impaired in intellectual disability

Alemany-González

Gener

Nebot

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…This study documents serum levels of EGCG in a mouse model of DS following controlled daily dosing of 200 mg/kg pure EGCG using oral gavage, confirming our hypothesis that this dose and route of EGCG treatment produced measurable levels of EGCG in the blood in Ts65Dn and euploid mice. Other experiments with considerably less EGCG in combination with other components have also shown measurable EGCG levels in the brain and bone of TgDyrk1A mice 31 . This experimenter-controlled gavage dosing contrasts with most other studies administering EGCG in DS mouse models that typically provide EGCG (or green tea extracts containing EGCG and other catechins) in the drinking water, in which the daily dosage and pattern of EGCG (or green tea extract) consumed over the day is controlled by the drinking behavior of the subject rather than directly by the experimenter.…”

Section: Discussionmentioning

confidence: 85%

Evaluation of the therapeutic potential of Epigallocatechin-3-gallate (EGCG) via oral gavage in young adult Down syndrome mice

Goodlett

Stringer

LaCombe

et al. 2020

Sci Rep

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Epigallocatechin-3-gallate (EGCG) is a candidate therapeutic for Down syndrome (DS) phenotypes based on in vitro inhibition of DYRK1A, a triplicated gene product of Trisomy 21 (Ts21). Consumption of green tea extracts containing eGcG improved some cognitive and behavioral outcomes in DS mouse models and in humans with Ts21. In contrast, treatment with pure EGCG in DS mouse models did not improve neurobehavioral phenotypes. This study tested the hypothesis that 200 mg/kg/day of pure EGCG, given via oral gavage, would improve neurobehavioral and skeletal phenotypes in the Ts65Dn DS mouse model. Serum EGCG levels post-gavage were significantly higher in trisomic mice than in euploid mice. Daily EGCG gavage treatments over three weeks resulted in growth deficits in both euploid and trisomic mice. Compared to vehicle treatment, EGCG did not significantly improve behavioral performance of Ts65Dn mice in the multivariate concentric square field, balance beam, or Morris water maze tasks, but reduced swimming speed. Furthermore, EGCG resulted in reduced cortical bone structure and strength in Ts65Dn mice. These outcomes failed to support the therapeutic potential of EGCG, and the deleterious effects on growth and skeletal phenotypes underscore the need for caution in high-dose eGcG supplements as an intervention in DS.

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“…A nutritional supplement enriched with EGCG (94% EGCG of total catechins) showed a normalization of relevant plasma and neuronal biomarkers in mice overexpressing DYRK1A, such as BDNF and NFkB. Moreover, EGCG was able to cross the blood-brain barrier, diffusing in the brain, and has demonstrated to be safe on liver and heart function [ 50 ].…”

Section: Resultsmentioning

confidence: 99%

Therapeutic Effects of Catechins in Less Common Neurological and Neurodegenerative Disorders

et al. 2021

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In recent years, neurological and neurodegenerative disorders research has focused on altered molecular mechanisms in search of potential pharmacological targets, e.g., imbalances in mechanisms of response to oxidative stress, inflammation, apoptosis, autophagy, proliferation, differentiation, migration, and neuronal plasticity, which occur in less common neurological and neurodegenerative pathologies (Huntington disease, multiple sclerosis, fetal alcohol spectrum disorders, and Down syndrome). Here, we assess the effects of different catechins (particularly of epigalocatechin-3-gallate, EGCG) on these disorders, as well as their use in attenuating age-related cognitive decline in healthy individuals. Antioxidant and free radical scavenging properties of EGCG -due to their phenolic hydroxyl groups-, as well as its immunomodulatory, neuritogenic, and autophagic characteristics, makes this catechin a promising tool against neuroinflammation and microglia activation, common in these pathologies. Although EGCG promotes the inhibition of protein aggregation in experimental Huntington disease studies and improves the clinical severity in multiple sclerosis in animal models, its efficacy in humans remains controversial. EGCG may normalize DYRK1A (involved in neural plasticity) overproduction in Down syndrome, improving behavioral and neural phenotypes. In neurological pathologies caused by environmental agents, such as FASD, EGCG enhances antioxidant defense and regulates placental angiogenesis and neurodevelopmental processes. As demonstrated in animal models, catechins attenuate age-related cognitive decline, which results in improvements in long-term outcomes and working memory, reduction of hippocampal neuroinflammation, and enhancement of neuronal plasticity; however, further studies are needed. Catechins are valuable compounds for treating and preventing certain neurodegenerative and neurological diseases of genetic and environmental origin. However, the use of different doses of green tea extracts and EGCG makes it difficult to reach consistent conclusions for different populations.

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Molecular Rescue of Dyrk1A Overexpression Alterations in Mice with Fontup® Dietary Supplement: Role of Green Tea Catechins

Cited by 17 publications

References 53 publications

Prefrontal–hippocampal functional connectivity encodes recognition memory and is impaired in intellectual disability

Prefrontal–hippocampal functional connectivity encodes recognition memory and is impaired in intellectual disability

Evaluation of the therapeutic potential of Epigallocatechin-3-gallate (EGCG) via oral gavage in young adult Down syndrome mice

Therapeutic Effects of Catechins in Less Common Neurological and Neurodegenerative Disorders

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