Green Tea & Down Syndrome Abstracts

Hum. Mol. Genet. (2015)

Rescue of the abnormal skeletal phenotype in Ts65Dn Down syndrome mice using genetic and therapeutic modulation of trisomic Dyrk1a

Joshua D. Blazek, Irushi Abeysekera, Jiliang Li and Randall J. Roper
Department of Biology, Indiana University-Purdue University Indianapolis and Indiana University Center for Regenerative Biology and Medicine, 723 W. Michigan Street, SL306, Indianapolis, IN 46202, USA.

Trisomy 21 causes skeletal alterations in individuals with Down syndrome (DS) but the causative trisomic gene and a therapeutic approach to rescue these abnormalities are unknown. Individuals with DS display skeletal alterations including reduced bone mineral density, modified bone structure and distinctive facial features. Due to peripheral skeletal anomalies and extended longevity, individuals with DS are increasingly more susceptible to bone fractures. Understanding the genetic and developmental origins of DS skeletal abnormalities would facilitate the development of therapies to rescue these and other deficiencies associated with DS. DYRK1A is found in three copies in individuals with DS and Ts65Dn DS mice and has been hypothesized to be involved in many Trisomy 21 phenotypes including skeletal abnormalities. Return of Dyrk1a copy number to normal levels in Ts65Dn mice rescued the appendicular bone abnormalities, suggesting that appropriate levels of DYRK1A expression are critical for the development and maintenance of the DS appendicular skeleton. Therapy using the DYRK1A inhibitor EGCG improved Ts65Dn skeletal phenotypes. These outcomes suggest that the osteopenic phenotype associated with DS may be rescued postnatally by targeting trisomic Dyrk1a.

Mol Nutr Food Res 58(2): 278-88 (2014 Sep)

Epigallocatechin-3-gallate, a DYRK1A inhibitor, rescues cognitive deficits in Down syndrome mouse models and in humans

De la Torre R, De Sola S, Pons M, Duchon A, de Lagran MM, Farré M, Fitó M, Benejam B, Langohr K, Rodriguez J, Pujadas M, Bizot JC, Cuenca A, Janel N, Catuara S, Covas MI, Blehaut H, Herault Y, Delabar JM, Dierssen M.
Human Pharmacology and Clinical Neurosciences Research Group-Neurosciences Program, IMIM-Hospital del Mar Research Institute, Barcelona, Spain; Cardiovascular Risk and Nutrition Research Group-Inflammatory and Cardiovascular Disorders Program, IMIM-Hospital del Mar Research Institute, and CIBER of Physiopathology of Obesity and Nutrition (CIBEROBN), Barcelona, Spain; University Pompeu Fabra, CEXS-UPF, Barcelona, Spain

SCOPE: Trisomy for human chromosome 21 results in Down syndrome (DS), which is among the most complex genetic perturbations leading to intellectual disability. Accumulating data suggest that overexpression of the dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (DYRK1A), is a critical pathogenic mechanisms in the intellectual deficit.
METHODS AND RESULTS: Here we show that the green tea flavonol epigallocatechin-gallate (EGCG), a DYRK1A inhibitor, rescues the cognitive deficits of both segmental trisomy 16 (Ts65Dn) and transgenic mice overexpressing Dyrk1A in a trisomic or disomic genetic background, respectively. It also significantly reverses cognitive deficits in a pilot study in DS individuals with effects on memory recognition, working memory and quality of life. We used the mouse models to ensure that EGCG was able to reduce DYRK1A kinase activity in the hippocampus and found that it also induced significant changes in plasma homocysteine levels, which were correlated with Dyrk1A expression levels. Thus, we could use plasma homocysteine levels as an efficacy biomarker in our human study.
CONCLUSION: We conclude that EGCG is a promising therapeutic tool for cognitive enhancement in DS, and its efficacy may depend of Dyrk1A inhibition.

J Neurosci 22;34(4): 1138-47 (2014 Jan)

Prefrontal Deficits in a Murine Model Overexpressing the Down Syndrome Candidate Gene Dyrk1a

Thomazeau A, Lassalle O, Iafrati J, Souchet B, Guedj F, Janel N, Chavis P, Delabar J, Manzoni OJ.
Institut National de la Santé et de la Recherche Médicale U901, Marseille, 13009, France, Université Aix-Marseille UMR S901, Marseille, 13009, France, INMED, Marseille, 13009, France, and Université Paris Diderot, Sorbonne Paris Cité, Adaptive Functional Biology, EAC Centre National de la Recherche Scientifique 4413, Paris, 75205, France

The gene Dyrk1a is the mammalian ortholog of Drosophila minibrain. Dyrk1a localizes in the Down syndrome (DS) critical region of chromosome 21q22.2 and is a major candidate for the behavioral and neuronal abnormalities associated with DS. PFC malfunctions are a common denominator in several neuropsychiatric diseases, including DS, but the contribution of DYRK1A in PFC dysfunctions, in particular the synaptic basis for impairments of executive functions reported in DS patients, remains obscure. We quantified synaptic plasticity, biochemical synaptic markers, and dendritic morphology of deep layer pyramidal PFC neurons in adult mBACtgDyrk1a transgenic mice that overexpress Dyrk1a under the control of its own regulatory sequences. We found that overexpression of Dyrk1a largely increased the number of spines on oblique dendrites of pyramidal neurons, as evidenced by augmented spine density, higher PSD95 protein levels, and larger miniature EPSCs. The dendritic alterations were associated with anomalous NMDAR-mediated long-term potentiation and accompanied by a marked reduction in the pCaMKII/CaMKII ratio in mBACtgDyrk1a mice. Retrograde endocannabinoid-mediated long-term depression (eCB-LTD) was ablated in mBACtgDyrk1a mice. Administration of green tea extracts containing epigallocatechin 3-gallate, a potent DYRK1A inhibitor, to adult mBACtgDyrk1a mice normalized long-term potentiation and spine anomalies but not eCB-LTD. However, inhibition of the eCB deactivating enzyme monoacylglycerol lipase normalized eCB-LTD in mBACtgDyrk1a mice. These data shed light on previously undisclosed participation of DYRK1A in adult PFC dendritic structures and synaptic plasticity. Furthermore, they suggest its involvement in DS-related endophenotypes and identify new potential therapeutic strategies.

Biochim Biophys Acta 1832(4): 542-52 (2013 Apr)

Epigallocatechin-3-gallate prevents oxidative phosphorylation deficit and promotes mitochondrial biogenesis in human cells from subjects with Down's syndrome

Valenti D, De Rasmo D, Signorile A, Rossi L, de Bari L, Scala I, Granese B, Papa S, Vacca RA.
Institute of Biomembranes and Bioenergetics, National Council of Research, Bari, Italy

A critical role for mitochondrial dysfunction has been proposed in the pathogenesis of Down's syndrome (DS), a human multifactorial disorder caused by trisomy of chromosome 21, associated with mental retardation and early neurodegeneration. Previous studies from our group demonstrated in DS cells a decreased capacity of the mitochondrial ATP production system and overproduction of reactive oxygen species (ROS) in mitochondria. In this study we have tested the potential of epigallocatechin-3-gallate (EGCG) - a natural polyphenol component of green tea - to counteract the mitochondrial energy deficit found in DS cells. We found that EGCG, incubated with cultured lymphoblasts and fibroblasts from DS subjects, rescued mitochondrial complex I and ATP synthase catalytic activities, restored oxidative phosphorylation efficiency and counteracted oxidative stress. These effects were associated with EGCG-induced promotion of PKA activity, related to increased cellular levels of cAMP and PKA-dependent phosphorylation of the NDUFS4 subunit of complex I. In addition, EGCG strongly promoted mitochondrial biogenesis in DS cells, as associated with increase in Sirt1-dependent PGC-1a deacetylation, NRF-1 and T-FAM protein levels and mitochondrial DNA content. In conclusion, this study shows that EGCG is a promoting effector of oxidative phosphorylation and mitochondrial biogenesis in DS cells, acting through modulation of the cAMP/PKA- and sirtuin-dependent pathways. EGCG treatment promises thus to be a therapeutic approach to counteract mitochondrial energy deficit and oxidative stress in DS.

PLoS One 4(2): e4606 (2009 Feb 26)

Green Tea Polyphenols Rescue of Brain Defects Induced by Overexpression of DYRK1A

Fayçal Guedj, Catherine Sébrié, Isabelle Rivals, Aurelie Ledru, Evelyne Paly, Jean C. Bizot, Desmond Smith, Edward Rubin, Brigitte Gillet, Mariona Arbones, Jean M. Delabar
Functional and Adaptive Biology, Université Paris Diderot-Paris7 and CNRS, Paris, France.

Individuals with partial HSA21 trisomies and mice with partial MMU16 trisomies containing an extra copy of the DYRK1A gene present various alterations in brain morphogenesis. They present also learning impairments modeling those encountered in Down syndrome. Previous MRI and histological analyses of a transgenic mice generated using a human YAC construct that contains five genes including DYRK1A reveal that DYRK1A is involved, during development, in the control of brain volume and cell density of specific brain regions. Gene dosage correction induces a rescue of the brain volume alterations. DYRK1A is also involved in the control of synaptic plasticity and memory consolidation. Increased gene dosage results in brain morphogenesis defects, low BDNF levels and mnemonic deficits in these mice. Epigallocatechin gallate (EGCG) — a member of a natural polyphenols family, found in great amount in green tea leaves — is a specific and safe DYRK1A inhibitor. We maintained control and transgenic mice overexpressing DYRK1A on two different polyphenol-based diets, from gestation to adulthood. The major features of the transgenic phenotype were rescued in these mice.

Neurochem Res 33(5):776-83 (2008 May)

Promotion of neuronal plasticity by (-)-epigallocatechin-3-gallate

Xie W1, Ramakrishna N, Wieraszko A, Hwang YW.
CSI/IBR Center for Developmental Neuroscience, College of Staten Island, City University of New York, Staten Island, NY 10314, USA

The consumption of (-)-epigallocatechin-3-gallate (EGCG), the major polyphenolic compound found in green tea, has been associated with various neurological benefits including cognitive improvement. The physiological basis for this effect is unknown. In this study, we used synaptic transmission between the CA3 and CA1 regions (Schaffer collateral) of the mouse hippocampus to examine the effects of EGCG on neuronal plasticity. We found that the level of high frequency stimulation-evoked long-term potentiation (LTP) was significantly enhanced when hippocampal slices were pre-incubated with 10 microM EGCG for 1 h prior to the experiment. EGCG incubation also enabled hippocampal slices prepared from Ts65Dn mice, a Down syndrome mouse model deficient in LTP, to express LTP to a level comparable to the normal controls. EGCG treatment did not alter the degree of pair-pulse inhibition; therefore, the enhancement effect of EGCG is unlikely to involve the attenuation of this inhibitory mechanism.