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| Consensus motif of phosphopeptides altered in transgenic mice overexpressing Dyrk1A. Graphical representation of the sequence conservation of amino acids in phosphopeptides upregulated (or exclusively present) in TG mice. The overall height of the stack indicates the sequence conservation at a given position, while the height of symbols within the stack indicates the relative frequency of each amino acid at that position. Polar amino acids are in green, neutral ones in purple, basic ones in blue, acidic ones in red, and hydrophobic ones in black. Stack width is scaled by the fraction of amino acids in the column. (A) Sequence logo with all phosphopeptides (98) upregulated (or exclusively present) in TG mice compared to WT mice. (B) All phosphopeptides in A with a phosphorylated serine, the most common site of phosphorylation (82). (C) All phosphopeptides in B with a proline in position + 1, the most common + 1 site (35). (D) All phosphopeptides in B with a proline in position -2, the most common -2 site (11).
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Down syndrome (DS), caused by trisomy of chromosome 21, is the most common genetic cause of intellectual disability. We recently discovered that green tea extracts containing epigallocatechin-3-gallate (EGCG) improve cognition in mice transgenic for Dyrk1a (TgDyrk1A) and in a trisomic DS mouse model (Ts65Dn). Interestingly, paired with cognitive st...
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... the phosphoproteome level, we identified 98 phosphopeptides-corresponding to 90 proteins-that increased their abundance in TG mice compared to their WT counterparts, and 105 phosphopeptides-mapping to 100 different proteins-that decreased their abundance (Tables 2, 3). To understand whether DYRK1A kinase activity could explain part of the changes in the phosphopeptide levels, we analyzed the phosphorylation motifs of the deregulated phosphopeptides creating a sequence logo ( Figure 1A). We found that 82 (out of the 98 phosphopeptides that increased their abundance in TG hippocampus, see above) had a phosphorylated serine ( Figure 1B), with 35 of them having also a proline in position + 1 (Figure 1C), and 11 having a proline in position -2 ( Figure 1D). ...
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... understand whether DYRK1A kinase activity could explain part of the changes in the phosphopeptide levels, we analyzed the phosphorylation motifs of the deregulated phosphopeptides creating a sequence logo ( Figure 1A). We found that 82 (out of the 98 phosphopeptides that increased their abundance in TG hippocampus, see above) had a phosphorylated serine ( Figure 1B), with 35 of them having also a proline in position + 1 (Figure 1C), and 11 having a proline in position -2 ( Figure 1D). PXSP is a known consensus motif for the ERK1/2/MAPK pathway, which has previously been linked with learning and memory (Peng et al., 2010), and DYRK1A, being a proline directed kinase, has an optimal phosphorylation sequence similar to ERK2. ...
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... understand whether DYRK1A kinase activity could explain part of the changes in the phosphopeptide levels, we analyzed the phosphorylation motifs of the deregulated phosphopeptides creating a sequence logo ( Figure 1A). We found that 82 (out of the 98 phosphopeptides that increased their abundance in TG hippocampus, see above) had a phosphorylated serine ( Figure 1B), with 35 of them having also a proline in position + 1 (Figure 1C), and 11 having a proline in position -2 ( Figure 1D). PXSP is a known consensus motif for the ERK1/2/MAPK pathway, which has previously been linked with learning and memory (Peng et al., 2010), and DYRK1A, being a proline directed kinase, has an optimal phosphorylation sequence similar to ERK2. ...
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... understand whether DYRK1A kinase activity could explain part of the changes in the phosphopeptide levels, we analyzed the phosphorylation motifs of the deregulated phosphopeptides creating a sequence logo ( Figure 1A). We found that 82 (out of the 98 phosphopeptides that increased their abundance in TG hippocampus, see above) had a phosphorylated serine ( Figure 1B), with 35 of them having also a proline in position + 1 (Figure 1C), and 11 having a proline in position -2 ( Figure 1D). PXSP is a known consensus motif for the ERK1/2/MAPK pathway, which has previously been linked with learning and memory (Peng et al., 2010), and DYRK1A, being a proline directed kinase, has an optimal phosphorylation sequence similar to ERK2. ...
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... this distribution, we detected 10 "protein hubs, " defined as those appearing in the 5% right tail of the node-degree distribution (Supplementary Figures S1A,B) with a node degree higher than 30. Of these 10 hubs, four were seed proteins of the TG network: SMAD3, PRNP, HRAS, and PTEN, while the others were primary interactors ( Table 4). ...
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... these 10 hubs, four were seed proteins of the TG network: SMAD3, PRNP, HRAS, and PTEN, while the others were primary interactors ( Table 4). With the exception of PRNP, which formed a sub-module in the network, the other nine hub proteins shared common interactors (Supplementary Figure S1C). Three hubs of the network are DYRK1A phosphorylation substrates: HRAS, GRB2, and TRP53. ...
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... we found 10 transcription factors that could explain the protein abundance changes observed in TG mice (Table 1), including FOXO1 that has been described as a DYRK1A substrate ( Woods et al., 2001;Yang et al., 2001). In addition, DYRK1A promotes both histone acetylation and deacetylation by phosphorylating SIRT1 (Guo et al., 2010), and CREB transcription factor, respectively ( Yang et al., 2001). It also interferes with chromatin remodeling by binding nBAF and reducing the levels of the NRSF/REST neuron-restrictive silencing factor ( Lepagnol-Bestel et al., 2009). ...
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... the phosphoproteome level, we identified 98 phosphopeptides-corresponding to 90 proteins-that increased their abundance in TG mice compared to their WT counterparts, and 105 phosphopeptides-mapping to 100 different proteins-that decreased their abundance (Tables 2, 3). To understand whether DYRK1A kinase activity could explain part of the changes in the phosphopeptide levels, we analyzed the phosphorylation motifs of the deregulated phosphopeptides creating a sequence logo ( Figure 1A). We found that 82 (out of the 98 phosphopeptides that increased their abundance in TG hippocampus, see above) had a phosphorylated serine ( Figure 1B), with 35 of them having also a proline in position + 1 (Figure 1C), and 11 having a proline in position -2 ( Figure 1D). ...
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... understand whether DYRK1A kinase activity could explain part of the changes in the phosphopeptide levels, we analyzed the phosphorylation motifs of the deregulated phosphopeptides creating a sequence logo ( Figure 1A). We found that 82 (out of the 98 phosphopeptides that increased their abundance in TG hippocampus, see above) had a phosphorylated serine ( Figure 1B), with 35 of them having also a proline in position + 1 (Figure 1C), and 11 having a proline in position -2 ( Figure 1D). PXSP is a known consensus motif for the ERK1/2/MAPK pathway, which has previously been linked with learning and memory (Peng et al., 2010), and DYRK1A, being a proline directed kinase, has an optimal phosphorylation sequence similar to ERK2. ...
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... understand whether DYRK1A kinase activity could explain part of the changes in the phosphopeptide levels, we analyzed the phosphorylation motifs of the deregulated phosphopeptides creating a sequence logo ( Figure 1A). We found that 82 (out of the 98 phosphopeptides that increased their abundance in TG hippocampus, see above) had a phosphorylated serine ( Figure 1B), with 35 of them having also a proline in position + 1 (Figure 1C), and 11 having a proline in position -2 ( Figure 1D). PXSP is a known consensus motif for the ERK1/2/MAPK pathway, which has previously been linked with learning and memory (Peng et al., 2010), and DYRK1A, being a proline directed kinase, has an optimal phosphorylation sequence similar to ERK2. ...
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... understand whether DYRK1A kinase activity could explain part of the changes in the phosphopeptide levels, we analyzed the phosphorylation motifs of the deregulated phosphopeptides creating a sequence logo ( Figure 1A). We found that 82 (out of the 98 phosphopeptides that increased their abundance in TG hippocampus, see above) had a phosphorylated serine ( Figure 1B), with 35 of them having also a proline in position + 1 (Figure 1C), and 11 having a proline in position -2 ( Figure 1D). PXSP is a known consensus motif for the ERK1/2/MAPK pathway, which has previously been linked with learning and memory (Peng et al., 2010), and DYRK1A, being a proline directed kinase, has an optimal phosphorylation sequence similar to ERK2. ...
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... this distribution, we detected 10 "protein hubs, " defined as those appearing in the 5% right tail of the node-degree distribution (Supplementary Figures S1A,B) with a node degree higher than 30. Of these 10 hubs, four were seed proteins of the TG network: SMAD3, PRNP, HRAS, and PTEN, while the others were primary interactors ( Table 4). ...
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... these 10 hubs, four were seed proteins of the TG network: SMAD3, PRNP, HRAS, and PTEN, while the others were primary interactors ( Table 4). With the exception of PRNP, which formed a sub-module in the network, the other nine hub proteins shared common interactors (Supplementary Figure S1C). Three hubs of the network are DYRK1A phosphorylation substrates: HRAS, GRB2, and TRP53. ...
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... we found 10 transcription factors that could explain the protein abundance changes observed in TG mice (Table 1), including FOXO1 that has been described as a DYRK1A substrate ( Woods et al., 2001;Yang et al., 2001). In addition, DYRK1A promotes both histone acetylation and deacetylation by phosphorylating SIRT1 (Guo et al., 2010), and CREB transcription factor, respectively ( Yang et al., 2001). It also interferes with chromatin remodeling by binding nBAF and reducing the levels of the NRSF/REST neuron-restrictive silencing factor ( Lepagnol-Bestel et al., 2009). ...
Citations
... Our behavioral experiments recapitulated the impaired performance previously reported in the Novel Object Recognition (De Toma et al. 2019). TG mice showed significantly reduced object discrimination, as described in other DS (Fernandez and Garner 2008) and transgenic Dyrk1A models (Guedj et al. 2009). ...
In this study, we investigated the impact of Dual specificity tyrosine-phosphorylation-regulated kinase 1A (Dyrk1A) overexpression, a gene associated with Down syndrome, on hippocampal neuronal deficits in mice. Our findings revealed that mice overexpressing Dyrk1A (TgDyrk1A; TG) exhibited impaired hippocampal recognition memory, disrupted excitation-inhibition balance, and deficits in long-term potentiation (LTP). Specifically, we observed layer-specific deficits in dendritic arborization of TG CA1 pyramidal neurons in the stratum radiatum. Through computational modeling, we determined that these alterations resulted in reduced storage capacity and compromised integration of inputs, with decreased high γ oscillations. Contrary to prevailing assumptions, our model suggests that deficits in neuronal architecture, rather than over-inhibition, primarily contribute to the reduced network. We explored the potential of environmental enrichment (EE) as a therapeutic intervention and found that it normalized the excitation-inhibition balance, restored LTP, and improved short-term recognition memory. Interestingly, we observed transient significant dendritic remodeling, leading to recovered high γ. However, these effects were not sustained after EE discontinuation. Based on our findings, we conclude that Dyrk1A overexpression-induced layer-specific neuromorphological disturbances impair the encoding of place and temporal context. These findings contribute to our understanding of the underlying mechanisms of Dyrk1A-related hippocampal deficits and highlight the challenges associated with long-term therapeutic interventions for cognitive impairments.
... Naturally occurring phytochemicals, and in particular polyphenols belonging to the class of flavonoids, have been deeply investigated as intriguing possibilities for the management of DS because of their multimodal actions in targeting and improving pathways, including regulatory genes and proteins of mitochondrial functions, disturbed by Hsa21 trisomy (see reviews [17,[147][148][149]). Several flavonoids, including epigallocatechin-3 gallate (EGCG), resveratrol (RSV) and 7,8-dihydroxyflavone (7,8-DHF), have been shown both in vitro and in mouse models of DS to target Sirt 1/ PGC-1α/AMPK pathways [123,132,150], to modulate expression and activity of DYRK1A [151,152] and the cyclic AMP responseelement binding protein (CREB) [153] and to potentially to regulate miR-155 [154], impacting mitochondria functions [16][17][18]147]. These polyphenols were able to fully rescue the activities of the defective MRC complex I and ATP synthase, increasing ATP production through OXPHOS, restoring the cellular and brain levels of ATP and decreasing mitochondrial ROS production and oxidative stress, with a consequent full restoration of hippocampal neurogenesis (for refs., see [132,147]). ...
Mitochondria, far beyond their prominent role as cellular powerhouses, are complex cellular organelles active as central metabolic hubs that are capable of integrating and controlling several signaling pathways essential for neurological processes, including neurogenesis and neuroplasticity. On the other hand, mitochondria are themselves regulated from a series of signaling proteins to achieve the best efficiency in producing energy, in establishing a network and in performing their own de novo synthesis or clearance. Dysfunctions in signaling processes that control mitochondrial biogenesis, dynamics and bioenergetics are increasingly associated with impairment in brain development and involved in a wide variety of neurodevelopmental disorders. Here, we review recent evidence proving the emerging role of mitochondria as master regulators of brain bioenergetics, highlighting their control skills in brain neurodevelopment and cognition. We analyze, from a mechanistic point of view, mitochondrial bioenergetic dysfunction as causally interrelated to the origins of typical genetic intellectual disability-related neurodevelopmental disorders, such as Down, Rett and Fragile X syndromes. Finally, we discuss whether mitochondria can become therapeutic targets to improve brain development and function from a holistic perspective.
... webpage, only around 50 trials are currently active in Down syndrome, and only a handful address cognitive impairment. More recent studies addressing DS-related intellectual disability include pulsatile treatment with GnRH, which reportedly improves cognition in patients with DS (Manfredi-Lozano et al. 2022), and treatment with green tea extracts containing epigallocatechin-3-gallate (EGCG), an inhibitor of Dyrk1a, in a trisomic DS mouse model (Ts65Dn) (De Toma et al. 2019;De Toma et al. 2020). Although these studies have not currently been successful, they point to the option of targeting cell signaling pathways that can be related to cognitive function. ...
Down syndrome (DS) is characterized by the trisomy of chromosome 21 and by cognitive deficits that have been related to neuronal morphological alterations in humans, as well as in animal models. The gene encoding for amyloid precursor protein (APP) is present in autosome 21, and its overexpression in DS has been linked to neuronal dysfunction, cognitive deficit, and Alzheimer’s disease-like dementia. In particular, the neuronal ability to extend processes and branching is affected. Current evidence suggests that APP could also regulate neurite growth through its role in the actin cytoskeleton, in part by influencing p21-activated kinase (PAK) activity. The latter effect is carried out by an increased abundance of the caspase cleavage-released carboxy-terminal C31 fragment. In this work, using a neuronal cell line named CTb, which derived from the cerebral cortex of a trisomy 16 mouse, an animal model of human DS, we observed an overexpression of APP, elevated caspase activity, augmented cleavage of the C-terminal fragment of APP, and increased PAK1 phosphorylation. Morphometric analyses showed that inhibition of PAK1 activity with FRAX486 increased the average length of the neurites, the number of crossings per Sholl ring, the formation of new processes, and stimulated the loss of processes. Considering our results, we propose that PAK hyperphosphorylation impairs neurite outgrowth and remodeling in the cellular model of DS, and therefore we suggest that PAK1 may be a potential pharmacological target.
... actin (De Toma et al., 2019;Schneider et al., 2015;Singh and Lauth, 2017). This was interesting to us as we had previously shown that Ablim3 downregulation in DGCs results in generation of MFT-filopodial contacts with PV INs, a process that is thought to depend on destabilization of branched F-actin in MFTs (Guo et al., 2018). ...
... We had previously shown that Ablim3 localizes to puncta adherens junctions in MFTs (visualized by immunostaining for zonula occludens 1, ZO1)-sites of stabilization of the MFT on dendritic shafts of CA3/CA2 neurons ( Figure 1D) (Guo et al., 2018;Rollenhagen and Lubke, 2010). Since experience or viral mediated downregulation of Ablim3 results in generation of MFT-filopodial contacts with PV INs (Guo et al., 2018;Twarkowski et al., 2022) and Dyrk1a phosphorylation of substrates may result in their degradation (De Toma et al., 2019;Schneider et al., 2015;Singh and Lauth, 2017;Thompson et al., 2015), we asked whether experience-dependent downregulation of Ablim3 in mossy fiber terminals is dependent on Dyrk1a. Towards this goal, we first generated hemizygous Dyrk1a mice (EIIaCre; Dyrk1a f/+ or Dyrk1a +/-) by breeding female EIIa-Cre mice with male Dyrk1a f/+ mice (Heffner et al., 2012;Thompson et al., 2015). ...
... Thus, mossy fiber recruitment of FFI in DG-CA3/CA2 circuits may also depend on increased PV IN excitability as shown for FFI in CA3-CA1 circuits (Campanac et al., 2013). Whether developmental, genetic or epigenetic programs involved in PV IN maturation, excitability and specification of synaptic connectivity are re-used to mediate activity-dependent changes in PV INs excitability and perisomatic inhibition in DG-CA3/CA2 circuits is to be determined (Allaway et al., 2021;Bernard et al., 2022;Dehorter et al., 2015;Exposito-Alonso and Rico, 2022;Favuzzi et al., 2019;Li et al., 2011;Uezu et al., 2016). ...
Heterozygous mutations in the Dual specificity tyrosine-phosphorylation-regulated kinase 1a Dyrk1a gene define a syndromic form of Autism Spectrum Disorder. The synaptic and circuit mechanisms mediating Dyrk1a functions in social cognition are unclear. Here, we identify a social experience-sensitive mechanism in hippocampal mossy fiber-parvalbumin interneuron (PV IN) synapses by which Dyrk1a recruits feedforward inhibition of CA3 and CA2 to promote social recognition. We employ genetic epistasis logic to identify a cytoskeletal protein, Ablim3, as a synaptic substrate of Dyrk1a. We demonstrate that Ablim3 downregulation in dentate granule cells of adult hemizygous Dyrk1a mice is sufficient to restore PV IN mediated inhibition of CA3 and CA2 and social recognition. Acute chemogenetic activation of PV INs in CA3/CA2 of adult hemizygous Dyrk1a mice also rescued social recognition. Together, these findings illustrate how targeting Dyrk1a synaptic and circuit substrates as “enhancers of Dyrk1a function” harbors potential to reverse Dyrk1a haploinsufficiency-associated circuit and cognition impairments.
Highlights
Dyrk1a in mossy fibers recruits PV IN mediated feed-forward inhibition of CA3 and CA2
Dyrk1a-Ablim3 signaling in mossy fiber-PV IN synapses promotes inhibition of CA3 and CA2
Downregulating Ablim3 restores PV IN excitability, CA3/CA2 inhibition and social recognition in Dyrk1a+/- mice
Chemogenetic activation of PV INs in CA3/CA2 rescues social recognition in Dyrk1a+/- mice
... A 42 mg/kg/day EGCG dose has also shown to retrieve deregulation of phosphoprotein in the hippocampus, reverse the kinome deregulation process, and restore the epigenetic profile. Because of all these potential pathways, green tea derivatives may enhance cognition [189][190][191][192]. EGCG therapy restores mitochondrial bioenergetics and biogenesis, which were significantly reduced in Down syndrome. ...
Neurodegenerative diseases exert an overwhelming socioeconomic burden all around the globe. They are mainly characterized by modified protein accumulation that might trigger various biological responses, including oxidative stress, inflammation, regulation of signaling pathways, and excitotoxicity. These disorders have been widely studied during the last decade in the hopes of developing symptom-oriented therapeutics. However, no definitive cure has yet been discovered. Tea is one of the world’s most popular beverages. The same plant, Camellia Sinensis (L.).O. Kuntze, is used to make green, black, and oolong teas. Green tea has been most thoroughly studied because of its anti-cancer, anti-obesity, antidiabetic, anti-inflammatory, and neuroprotective properties. The beneficial effect of consumption of tea on neurodegenerative disorders has been reported in several human interventional and observational studies. The polyphenolic compounds found in green tea, known as catechins, have been demonstrated to have many therapeutic effects. They can help in preventing and, somehow, treating neurodegenerative diseases. Catechins show anti-inflammatory as well as antioxidant effects via blocking cytokines’ excessive production and inflammatory pathways, as well as chelating metal ions and free radical scavenging. They may inhibit tau protein phosphorylation, amyloid beta aggregation, and release of apoptotic proteins. They can also lower alpha-synuclein levels and boost dopamine levels. All these factors have the potential to affect neurodegenerative disorders. This review will examine catechins’ neuroprotective effects by highlighting their biological, pharmacological, antioxidant, and metal chelation abilities, with a focus on their ability to activate diverse cellular pathways in the brain. This review also points out the mechanisms of catechins in various neurodegenerative and cognitive diseases, including Alzheimer’s, Parkinson’s, multiple sclerosis, and cognitive deficit.
... This protein therefore plays a major role in cognitive dysfunctions linked with DS. Indeed, DYRK1A imbalance impacts the brain development, including pathways implicated in neurogenesis/neuroplasticity as well as synaptogenesis/synaptoplasticity [60,61]. More and more studies in mice focus their research on normalizing DYRK1A expression levels for therapeutic approaches for its multitude of interactions with many substrates (dynamin1, amphiphysin, tau protein, etc.) involved in cell cycle regulation and neuronal synaptic plasticity at different steps of development [62]. ...
... However, the beneficial outcomes were lost after one month [75]. EGCG at 42 mg/kg/day for one month rescued phosphoprotein deregulation in the hippocampus of Ts65Dn mice, reversing the kinome deregulation process and restoring the epigenetic profile, the beneficial effect in plasticity alterations being more beneficial if the treatment started during the first years of life [61,76]. ...
Plant-derived polyphenols flavonoids are increasingly being recognized for their medicinal potential. These bioactive compounds derived from plants are gaining more interest in ameliorating adverse health risks because of their low toxicity and few side effects. Among them, therapeutic approaches demonstrated the efficacy of catechins, a major group of flavonoids, in reverting several aspects of Down syndrome, the most common genomic disorder that causes intellectual disability. Down syndrome is characterized by increased incidence of developing Alzheimer’s disease, obesity, and subsequent metabolic disorders. In this focused review, we examine the main effects of catechins on comorbidities linked with Down syndrome. We also provide evidence of catechin effects on DYRK1A, a dosage-sensitive gene encoding a protein kinase involved in brain defects and metabolic disease associated with Down syndrome.
... As observed in a previous study (De Toma et al., 2019), EE mice tended to display higher DIs than NE mice (0.47 ± 0.09 vs. 0.37 ± 0.06), but this difference did not reach significance (unpaired T test, P = 0.36; Fig. 2B). This was likely due to ceiling effects on behavioral performance. ...
Rich social, physical, and cognitively stimulating lifestyles have powerful effects on cognitive abilities, especially when they are experienced early in life. Cognitive therapies are widely used to attenuate cognitive impairment due to intellectual disability, but also aging and neurodegeneration, however the underlying neural mechanisms are poorly understood. Here we investigated the neural substrates of memory amelioration induced by postnatal environmental enrichment (EE) in diploid female mice and Ts65Dn female mice with partial trisomy of genes ortholog to human chromosome 21, a standard model of Down syndrome (DS, trisomy 21). We recorded neural activities in two brain structures key for cognitive function, the hippocampus and the prefrontal cortex, during rest, sleep and memory performance in mice reared in standard or enriched environments for 7 weeks post-weaning. We found that EE shaped hippocampal-prefrontal neural dynamics in diploid mice and rescued the same disrupted pathways in Ts65Dn mice. The neural activity changes detected in EE-reared wild-type mice combined task-independent adjustments (augmented hippocampal pyramidal activity and gamma synchrony across different brain states) and memory-dependent adjustments (enhanced theta-gamma coupling and ripples in the HPC). Therefore, both brain state adjustments and memory-associated adjustments are good candidates to underlie the beneficial effects of EE on cognition in diploid female mice. Concomitantly, EE attenuated hippocampal and prefrontal hypersynchrony in trisomic females, suggesting distinct neural mechanisms for the generation and rescue of healthy and pathological brain synchrony, respectively, by EE. These results put forward hippocampal hypersynchrony and hippocampal-prefrontal miscommunication as major neural mechanisms underlying the beneficial effects of EE for intellectual disability in DS.
... EGCG has been shown to attenuate cognitive impairment in rodent models of Alzheimer's disease, improving spatial learning and long-term recognition memory in PS2Tg2576 mice (Kim et al., 2019) and enhancing working memory and spatial learning in APP/PS1 transgenic mice (Bao et al., 2020;Ettcheto et al., 2020). Furthermore, recognition memory and spatial working memory deficits are alleviated by green tea extract in genetic models of Down syndrome (Feki and Hibaoui, 2018;De Toma et al., 2019). ...
Epigallocatechin-3-gallate (EGCG) and caffeine are the two primary compounds found in green tea. While EGCG has anxiolytic and anti-inflammatory effects, its acute effects on cognition are not well understood. Furthermore, despite widespread green tea consumption, little is known about how EGCG and caffeine co-administration impacts behavior. Here, we investigated the effects of multiple doses of either EGCG or caffeine on a rat model of risk-taking. This was assessed using the risky decision-making task (RDT), in which rats choose between a small, well-tolerated reward and a large reward with escalating risk of mild footshock. Rats were tested in RDT after acute systemic administration of EGCG, caffeine or joint EGCG and caffeine. EGCG caused a dose-dependent reduction in risk-taking without affecting reward discrimination or task engagement. Caffeine did not impact risk-taking, but elevated locomotor activity and reduced task engagement at high doses. Finally, exposure to both EGCG and caffeine had no effect on risk-taking, suggesting that low-dose caffeine is sufficient to mask the risk-aversion caused by EGCG. These data suggest EGCG as a potential therapeutic treatment for psychological disorders that induce compulsive risky decision-making.
... L'équipe a notamment mis en évidence une action directe de DYRK1A phosphorylant la protéine SYN1 (synapsine1) sur son résidu sérine 551 et que le niveau de phosphorylation de ce résidu était proportionnel à la quantité de protéine DYRK1A présente. Plus tard, une seconde étude soulignera également une altération de la synapse dans le cas d'une surexpression de DYRK1A en modèle murin(De Toma et al., 2019). Enfin, très récemment, une troisième équipe a étudié le phospho-protéome associé à une inhibition de DYRK1A en utilisant l'inhibiteur de DYRK1A L41(Recassens et al., 2021). ...
La déficience intellectuelle (DI) est un trouble du neurodéveloppement et la première raison de consultation génétique. Cependant, un certain nombre de variants restent classés en tant que Variants de signification inconnue (VSI) et contribuent au phénomène d’errance diagnostique. De plus, la DI est caractérisée par une hétérogénéité génétique extrême et les mécanismes physiopathologiques associés sont généralement mal connues. Mon travail de doctorat a consisté à mettre au point des approches expérimentales permettant de reclasser l’ensemble des VSI dans les gènes DYRK1A et PQBP1. J’ai également investigué les mécanismes cellulaires dérégulés lors de l’inactivation de ces gènes dans un modèle de précurseurs neuronaux. Mes travaux de doctorat permettront donc d’améliorer le diagnostic moléculaire de la déficience intellectuelle associée à des mutations dans les gènes DYRK1A et PQBP1. Ils permettront également de mieux comprendre les mécanismes physiopathologiques impliqués dans ces troubles neurodéveloppementaux. Ces connaissances aideront à mieux prendre en charge les individus atteints et pourront permettre d’identifier de nouvelles cibles thérapeutiques.
... Some studies in Ts65Dn mouse models have shown that environmental enrichment (EE) associated with EGCG treatment at an average dose of 30 mg/kg/day enhances learning and memory in the cortex and hippocampus, preventing cognitive degeneration [96,100] and at 42 mg/kg/day rescues phosphoprotein deregulation in the hippocampus, restoring the epigenetic profile and reversing the kinome deregulation process. These mechanisms may promote the cognitive improvement induced by green tea derivatives [105,106]. Other experimental studies analyzing cell cultures or neural progenitor cells (NPCs) isolated from the hippocampus of Ts65Dn mice, revealed that EGCG treatment reactivated mitochondria bioenergetics and biogenesis, severely compromised in DS, and promoted neuronal progenitor cell proliferation with helpful effects on neuronal plasticity impeding the production of ROS [101,102]. ...
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.
