The polyphenols resveratrol and epigallocatechin-3-gallate restore the severe impairment of mitochondria in hippocampal progenitor cells from a Down syndrome mouse model

Abstract

Mitochondrial dysfunctions critically impair nervous system development and are potentially involved in the pathogenesis of various neurodevelopmental disorders, including Down syndrome (DS), the most common genetic cause of intellectual disability. Previous studies from our group demonstrated impaired mitochondrial activity in peripheral cells from DS subjects and the efficacy of epigallocatechin-3-gallate (EGCG) - a natural polyphenol major component of green tea - to counteract the mitochondrial energy deficit. In this study, to gain insight into the possible role of mitochondria in DS intellectual disability, mitochondrial functions were analyzed in neural progenitor cells (NPCs) isolated from the hippocampus of Ts65Dn mice, a widely used model of DS which recapitulates many major brain structural and functional phenotypes of the syndrome, including impaired hippocampal neurogenesis. We found that, during NPC proliferation, mitochondrial bioenergetics and mitochondrial biogenic program were strongly compromised in Ts65Dn cells, but not associated with free radical accumulation. These data point to a central role of mitochondrial dysfunction as an inherent feature of DS and not as a consequence of cell oxidative stress. Further, we disclose that, besides EGCG, also the natural polyphenol resveratrol, which displays a neuroprotective action in various human diseases but never tested in DS, restores oxidative phosphorylation efficiency and mitochondrial biogenesis, and improves proliferation of NPCs. These effects were associated with the activation of PGC-1α/Sirt1/AMPK axis by both polyphenols. This research paves the way for using nutraceuticals as a potential therapeutic tool in preventing or managing some energy deficit-associated DS clinical manifestations.

Early-Life Exposure to Lead Induces Cognitive Impairment in Elder Mice Targeting SIRT1 Phosphorylation and Oxidative Alterations

“…Of these, the fact that phosphorylation levels of SIRT1 and AMPK in Pb-exposed mice were restored by resveratrol treatment reflected the action of resveratrol on SIRT1/AMPK activation. Moreover, it is reported that resveratrol can promote SIRT1/AMPK activation (Valenti et al, 2016) and is implicated in neural plasticity (Torres-Pérez et al, 2015; Dias et al, 2016; Tian et al, 2016). Similar to our results for pSIRT1, the present study showed probe time in target area of the MWM test was also positively correlated with the ratio of pAMPK/AMPK which enhanced the link between cognition and resveratrol involving AMPK.…”

Mitophagy Transcriptome: Mechanistic Insights into Polyphenol-Mediated Mitophagy

“…For example, resveratrol has been shown to ameliorate mitochondrial bioenergetics and biogenic impairments in neuronal progenitor cells of the Down syndrome mice model. Resveratrol mitigates by activating mitochondrial biogenesis via PGC-1 α -SIRT1-AMPK signalling and restoring mitochondrial oxidative phosphorylation capabilities [102]. Low doses of resveratrol also protect against respiration dysfunction induced by mitochondrial mutations in patient-derived fibroblast cells [103].…”

Modeling Down syndrome in animals from the early stage to the 4.0 models and next

“…Energy metabolism was found to be perturbed in both human DS cell lines and mouse DS models, leading to increased production of reactive oxygen species (ROS) production (Shukkur et al, 2006, Conti et al, 2007, Valenti et al, 2010, Valenti et al, 2011, Brault et al, 2015. Ts1Cje mice were shown to have deficit in mitochondrial membrane potential and ATP production (Shukkur et al, 2006), while muscles from Ts3Yah mice were found to have decreased mitochondrial content and a slight increase in mitochondrial membrane permeability (Brault et al, 2015) and Ts65Dn hippocampal neuronal progenitor cells (NPCs) were found to be impaired in mitochondrial ATP synthesis and biogenesis (Valenti et al, 2016, Valenti et al, 2017. Those defects have been linked to alteration of the PGC1α/Sirt1/AMPK axis (Piccoli et al, 2013, Valenti et al, 2016, of the cAMP/PKA pathway and of proteins involved in mitochondrial fusion (Izzo et al, 2017, Valenti et al, 2017.…”

“…Ts1Cje mice were shown to have deficit in mitochondrial membrane potential and ATP production (Shukkur et al, 2006), while muscles from Ts3Yah mice were found to have decreased mitochondrial content and a slight increase in mitochondrial membrane permeability (Brault et al, 2015) and Ts65Dn hippocampal neuronal progenitor cells (NPCs) were found to be impaired in mitochondrial ATP synthesis and biogenesis (Valenti et al, 2016, Valenti et al, 2017. Those defects have been linked to alteration of the PGC1α/Sirt1/AMPK axis (Piccoli et al, 2013, Valenti et al, 2016, of the cAMP/PKA pathway and of proteins involved in mitochondrial fusion (Izzo et al, 2017, Valenti et al, 2017. Hsa21 genes having a role in energy and ROS metabolism are numerous: the MRPL39 and MRPS6 genes coding for mitochondrial ribosomal proteins, ATP5J and ATP5O encoding subunits of the mitochondrial ATP synthase, NDUFV3 encoding a subunit of the NADH-ubiquinone oxidoreductase complex of the respiratory chain or GABPA encoding a subunit of the nuclear respiratory transcription factor involved in activation of cytochrome oxidase expression and nuclear control of mitochondrial function.…”