Aerobic exercise and a BDNF-mimetic therapy rescue learning and memory in a mouse model of Down syndrome

Parrini, Martina; Ghezzi, Diego; Deidda, Gabriele; Medrihan, Lucian; Castroflorio, Enrico; Alberti, Micol; Baldelli, Pietro; Cancedda, Laura; Contestabile, Andrea

doi:10.1038/s41598-017-17201-8

Cited by 62 publications

(61 citation statements)

References 159 publications

(233 reference statements)

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“…Previous results have already demonstrated the beneficial effect of polyphenol-based diets on BDNF mRNA level in another model of mice overexpressing Dyrk1A [6]. Another study has investigated the use of a pharmacological approach indented to promote BDNF in Ts65Dn mice, a mouse model of DS, and provide evidence that the BDNF-mimetic drug 7,8-dihydroxyflavone rescued learning and memory impairments [39]. We here demonstrate the beneficial effect of FontUp ® administration on BDNF protein level in TgBACDyrk1A.…”

Section: Discussionsupporting

confidence: 65%

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

Moroy

Paul

et al. 2020

IJMS

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Epigallocatechin gallate (EGCG) is an inhibitor of DYRK1A, a serine/threonine kinase considered to be a major contributor of cognitive dysfunctions in Down syndrome (DS). Two clinical trials in adult patients with DS have shown the safety and efficacy to improve cognitive phenotypes using commercial green tea extract containing EGCG (45% content). In the present study, we performed a preclinical study using FontUp®, a new nutritional supplement with a chocolate taste specifically formulated for the nutritional needs of patients with DS and enriched with a standardized amount of EGCG in young mice overexpressing Dyrk1A (TgBACDyrk1A). This preparation is differential with previous one used, because its green tea extract has been purified to up 94% EGCG of total catechins. We analyzed the in vitro effect of green tea catechins not only for EGCG, but for others residually contained in FontUp®, on DYRK1A kinase activity. Like EGCG, epicatechin gallate was a noncompetitive inhibitor against ATP, molecular docking computations confirming these results. Oral FontUp® normalized brain and plasma biomarkers deregulated in TgBACDyrk1A, without negative effect on liver and cardiac functions. We compared the bioavailability of EGCG in plasma and brain of mice and have demonstrated that EGCG had well crossed the blood-brain barrier.

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Section: Discussionsupporting

confidence: 65%

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

Moroy

Paul

et al. 2020

IJMS

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“…Aberrant expression of BDNF is reported in DS patients and mouse models of DS [29–31], suggesting a relationship between neuronal development and BDNF in DS. BDNF is secreted extracellularly and mediates neuronal development and survival.…”

Section: Discussionmentioning

confidence: 99%

Altered development of dopaminergic neurons differentiated from stem cells from human exfoliated deciduous teeth of a patient with Down syndrome

et al. 2018

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BackgroundDown syndrome (DS) is a common developmental disorder resulting from the presence of an additional copy of chromosome 21. Abnormalities in dopamine signaling are suggested to be involved in cognitive dysfunction, one of the symptoms of DS, but the pathophysiological mechanism has not been fully elucidated at the cellular level. Stem cells from human exfoliated deciduous teeth (SHED) can be prepared from the dental pulp of primary teeth. Importantly, SHED can be collected noninvasively, have multipotency, and differentiate into dopaminergic neurons (DN). Therefore, we examined dopamine signaling in DS at the cellular level by isolating SHED from a patient with DS, differentiating the cells into DN, and examining development and function of DN.MethodsHere, SHED were prepared from a normal participant (Ctrl-SHED) and a patient with DS (DS-SHED). Initial experiments were performed to confirm the morphological, chromosomal, and stem cell characteristics of both SHED populations. Next, Ctrl-SHED and DS-SHED were differentiated into DN and morphological analysis of DN was examined by immunostaining. Functional analysis of DN was performed by measuring extracellular dopamine levels under basal and glutamate-stimulated conditions. In addition, expression of molecules involved in dopamine homeostasis was examined by quantitative real-time polymerase chain reaction and immunostaining. Statistical analysis was performed using two-tailed Student’s t-tests.ResultsCompared with Ctrl-SHED, DS-SHED showed decreased expression of nestin, a neural stem-cell marker. Further, DS-SHED differentiated into DN (DS-DN) exhibiting decreased neurite outgrowth and branching compared with Ctrl-DN. In addition, DS-DN dopamine secretion was lower than Ctrl-DN dopamine secretion. Moreover, aberrant expression of molecules involved in dopaminergic homeostasis was observed in DS-DN.ConclusionsOur results suggest that there was developmental abnormality and DN malfunction in the DS-SHED donor in this study. In the future, to clarify the detailed mechanism of dopamine-signal abnormality due to DN developmental and functional abnormalities in DS, it is necessary to increase the number of patients for analysis. Non-invasively harvested SHED may be very useful in the analysis of DS pathology.Electronic supplementary materialThe online version of this article (10.1186/s12883-018-1140-2) contains supplementary material, which is available to authorized users.

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“…Exercise mediates these beneficial responses by inducing neurogenesis (van Praag et al, 1999) and improving learning and memory formation (Vaynman et al, 2004(Vaynman et al, , 2006Berchtold et al, 2010). The positive changes observed in the brain after exercise are mediated by the induction of BDNF expression in the hippocampus (Neeper et al, 1995;Oliff et al, 1998;Tong et al, 2001;Berchtold et al, 2005) and the activation of its tropomyosin kinase receptor B (TRKB) receptor (Vaynman et al, 2004;Real et al, 2013;Parrini et al, 2017). Indeed, blocking BDNF signaling in the hippocampus attenuates exercise-induced learning and memory formation (Vaynman et al, 2004;García-Mesa et al, 2014;Kim and Leem, 2016).…”

Section: Introductionmentioning

confidence: 99%

Lactate mediates the effects of exercise on learning and memory through SIRT1-dependent activation of hippocampal brain-derived neurotrophic factor (BDNF)

Hayek¹,

Khalifeh²,

Zibara³

et al. 2019

J. Neurosci.

296

317

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Exercise promotes learning and memory formation. These effects depend on increases in hippocampal BDNF, a growth factor associated with cognitive improvement and the alleviation of depression symptoms. Identifying molecules that are produced during exercise and that mediate hippocampal Bdnf expression will allow us to harness the therapeutic potential of exercise. Here, we report that an endogenous molecule produced during exercise in male mice induces the Mus musculus Bdnf gene and promotes learning and memory formation. The metabolite lactate, which is released during exercise by the muscles, crosses the blood-brain barrier and induces Bdnf expression and TRKB signaling in the hippocampus. Indeed, we find that lactate-dependent increases in BDNF are associated with improved spatial learning and memory retention. The action of lactate is dependent on the activation of the Sirtuin1 deacetylase. SIRT1 increases the levels of the transcriptional coactivator PGC1a and the secreted molecule FNDC5, known to mediate Bdnf expression. These results reveal an endogenous mechanism to explain how physical exercise leads to the induction of BDNF, and identify lactate as a potential endogenous molecule that may have therapeutic value for CNS diseases in which BDNF signaling is disrupted.It is established that exercise promotes learning and memory formation and alleviates the symptoms of depression. These effects are mediated through inducing Bdnf expression and signaling in the hippocampus. Understanding how exercise induces Bdnf and identifying the molecules that mediate this induction will allow us to design therapeutic strategies that can mimic the effects of exercise on the brain, especially for patients with CNS disorders characterized by a decrease in Bdnf expression and who cannot exercise because of their conditions. We identify lactate as an endogenous metabolite that is produced during exercise, crosses the blood-brain barrier and promotes hippocampal dependent learning and memory in a BDNF-dependent manner. Our work identifies lactate as a component of the "exercise pill."

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Aerobic exercise and a BDNF-mimetic therapy rescue learning and memory in a mouse model of Down syndrome

Cited by 62 publications

References 159 publications

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

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

Altered development of dopaminergic neurons differentiated from stem cells from human exfoliated deciduous teeth of a patient with Down syndrome

Lactate mediates the effects of exercise on learning and memory through SIRT1-dependent activation of hippocampal brain-derived neurotrophic factor (BDNF)

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