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

• Published in: Biochimica et biophysica acta Vol. 1862; no. 6; pp. 1093 - 1104
• Main Authors: Valenti, Daniela, de Bari, Lidia, de Rasmo, Domenico, Signorile, Anna, Henrion-Caude, Alexandra, Contestabile, Andrea, Vacca, Rosa Anna
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.06.2016
• Subjects: Adenosine Triphosphate - metabolism; AMPK; Animals; Antioxidants - therapeutic use; Catechin - analogs & derivatives; Catechin - therapeutic use; Cell Proliferation - drug effects; Cells, Cultured; Disease Models, Animal; Down syndrome; Down Syndrome - drug therapy; Down Syndrome - metabolism; Down Syndrome - physiopathology; Female; Hippocampus - cytology; Hippocampus - drug effects; Hippocampus - metabolism; Hippocampus - physiopathology; Male; Mice; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondria - pathology; Mitochondrial bioenergetics; Mitochondrial biogenesis; Neural Stem Cells - cytology; Neural Stem Cells - drug effects; Neural Stem Cells - metabolism; Neural Stem Cells - pathology; Neurogenesis - drug effects; Neuroprotective Agents - therapeutic use; Nutraceuticals; PGC-1α; Protein Kinases - metabolism; Resveratrol - therapeutic use; HK; mtDNA; Mitochondrial bioenergetics; OLIGO; OXPHOS; FCCP; TMPD; T-FAM; DS; ASC; HOVA; Mitochondrial biogenesis; NRF-1; wt; gDNA; Nutraceuticals; AA; CC; Ap5A; SUCC; DCF; EGCG; SOD; PGC-1α; CN; ROS-ds; Down syndrome; DCFH-DA; RSV; G6P-DH; GLU/MAL; NPCs; ROT; ROS; POX; AMPK; AICAR; GAPDH; BrdU; PGC-1 α; MRC
• ISSN: 0925-4439; 0006-3002; 1879-260X
• DOI: 10.1016/j.bbadis.2016.03.003

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. •Neural progenitor cell (NPC) proliferation is affected in Ts65Dn model of DS.•Mitochondrial bioenergetics and biogenesis are impaired during NPC proliferation.•EGCG and RSV counteract mitochondrial dysfunctions and promote NPC proliferation.•EGCG and RSV activate PGC-1α/Sirt1/AMPK axis.