title: 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.
authors.affiliation: Institute of Biomembranes and Bioenergetics, National Council of Research, Bari, Italy. Electronic address: d.valenti@ibbe.cnr.it.
authors.forename: Daniela
authors.initials: D
authors.lastname: Valenti
authors.affiliation: Institute of Biomembranes and Bioenergetics, National Council of Research, Bari, Italy.
authors.forename: Lidia
authors.initials: L
authors.lastname: de Bari
authors.affiliation: Institute of Biomembranes and Bioenergetics, National Council of Research, Bari, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: de Rasmo
authors.affiliation: Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Signorile
authors.affiliation: INSERM UMR1163, Université Paris Descartes, Institut Imagine, Paris, France; Hôpital Necker-Enfants Malades, Paris, France.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Henrion-Caude
authors.affiliation: Neuroscience and Brain Technologies Department, Istituto Italiano di Tecnologia, Genova, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Contestabile
authors.affiliation: Institute of Biomembranes and Bioenergetics, National Council of Research, Bari, Italy. Electronic address: r.vacca@ibbe.cnr.it.
authors.forename: Rosa Anna
authors.initials: RA
authors.lastname: Vacca
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D002392:Catechin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D058953:Neural Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D055495:Neurogenesis / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000627:therapeutic use; D011494:Protein Kinases / Q000378:metabolism; D000077185:Resveratrol / Q000627:therapeutic use*
chemical_list: D000975:Antioxidants; D018696:Neuroprotective Agents; D000255:Adenosine Triphosphate; D002392:Catechin; C045651:epigallocatechin gallate; D011494:Protein Kinases; D000091162:AMP-Activated Protein Kinase Kinases; D000077185:Resveratrol
keywords: AMPK; Down syndrome; Mitochondrial bioenergetics; Mitochondrial biogenesis; Nutraceuticals; PGC-1α