Impaired Brain Mitochondrial Bioenergetics in the Ts65Dn Mouse Model of Down Syndrome Is Restored by Neonatal Treatment with the Polyphenol 7,8-Dihydroxyflavone.

Daniela Valenti,Rosa Anna Vacca,Marco Emili,Sandra Guidi,Renata Bartesaghi,Fiorenza Stagni

doi:10.3390/antiox11010062

Abstract

Down syndrome (DS), a major genetic cause of intellectual disability, is characterized by numerous neurodevelopmental defects. Previous in vitro studies highlighted a relationship between bioenergetic dysfunction and reduced neurogenesis in progenitor cells from the Ts65Dn mouse model of DS, suggesting a critical role of mitochondrial dysfunction in neurodevelopmental alterations in DS. Recent in vivo studies in Ts65Dn mice showed that neonatal supplementation (Days P3–P15) with the polyphenol 7,8-dihydroxyflavone (7,8-DHF) fully restored hippocampal neurogenesis. The current study was aimed to establish whether brain mitochondrial bioenergetic defects are already present in Ts65Dn pups and whether early treatment with 7,8-DHF positively impacts on mitochondrial function. In the brain and cerebellum of P3 and P15 Ts65Dn pups we found a strong impairment in the oxidative phosphorylation apparatus, resulting in a deficit in mitochondrial ATP production and ATP content. Administration of 7,8-DHF (dose: 5 mg/kg/day) during Days P3–P15 fully restored bioenergetic dysfunction in Ts65Dn mice, reduced the levels of oxygen radicals and reinstated the hippocampal levels of PGC-1α. No pharmacotherapy is available for DS. From current findings, 7,8-DHF emerges as a treatment with a good translational potential for improving mitochondrial bioenergetics and, thus, mitochondria-linked neurodevelopmental alterations in DS.

Highlights

Published: 28 December 2021Triplication of human chromosome 21 (Hsa21) causes Down syndrome (DS), which represents the most frequent genetic abnormality leading to intellectual disability
To establish whether mitochondrial bioenergetics is already compromised during neonatal life stages in the Ts65Dn mouse model of DS, we first carried out a functional analysis of the mitochondrial bioenergetic efficiency in the brain of neonate mice
The rate of mitochondrial ATP synthesis was strongly reduced in brain mitochondria from both P3 (Figure 1A) and P15 (Figure 1B) Ts65Dn mice compared to their euploid controls, when either glutamate plus malate (GLU/MAL) or SUCC were used as the energy substrates

Summary

Introduction

Published: 28 December 2021Triplication of human chromosome 21 (Hsa21) causes Down syndrome (DS), which represents the most frequent genetic abnormality leading to intellectual disability. DS presents neuropathological phenotypes that are already detectable during foetal life and infancy and bring about alterations in brain development [1]. The brains from subjects with DS show structural and functional abnormalities, including reduced volume, lower neuronal density and abnormal synaptic plasticity [2]. Neural stem cells proliferate and differentiate into neurons in a process called neurogenesis [3]. In the hippocampus, neurogenesis is not limited to the prenatal period, but continues throughout life as an adaptive response regulating brain plasticity and memory [4]. Results obtained using different model systems, including brain biopsies from DS subjects, DS mouse models and neural progenitor cells (NPCs) derived from the hippocampus of mouse

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