S100B and APP Promote a Gliocentric Shift and Impaired Neurogenesis in Down Syndrome Neural Progenitors

Jie Lu,Volney Sheen,Giuseppe Esposito,Laurent C Delli-Bovi,Jonathan L Hecht,Caterina Scuderi,Christopher J Chang,Bryan C Dickinson,Luca Steardo,Takashi Mori

doi:10.1371/journal.pone.0022126

Abstract

Down syndrome (DS) is a developmental disorder associated with mental retardation (MR) and early onset Alzheimer's disease (AD). These CNS phenotypes are attributed to ongoing neuronal degeneration due to constitutive overexpression of chromosome 21 (HSA21) genes. We have previously shown that HSA21 associated S100B contributes to oxidative stress and apoptosis in DS human neural progenitors (HNPs). Here we show that DS HNPs isolated from fetal frontal cortex demonstrate not only disturbances in redox states within the mitochondria and increased levels of progenitor cell death but also transition to more gliocentric progenitor phenotypes with a consequent reduction in neuronogenesis. HSA21 associated S100B and amyloid precursor protein (APP) levels are simultaneously increased within DS HNPs, their secretions are synergistically enhanced in a paracrine fashion, and overexpressions of these proteins disrupt mitochondrial membrane potentials and redox states. HNPs show greater susceptibility to these proteins as compared to neurons, leading to cell death. Ongoing inflammation through APP and S100B overexpression further promotes a gliocentric HNPs phenotype. Thus, the loss in neuronal numbers seen in DS is not merely due to increased HNPs cell death and neurodegeneration, but also a fundamental gliocentric shift in the progenitor pool that impairs neuronal production.

Highlights

Down syndrome (DS) arises from a triplication of genes on chromosome 21 (HSA21) and is characterized by neurological complications including mental retardation and early onset Alzheimer’s disease (AD) [1]
While increased reactive oxygen species (ROS), apoptosis and gliosis have been implicated in postnatal DS neurons [3,12,13,14], few studies have addressed whether the same endophenotypes are apparent during cortical development
To address the possible mitochondrial involvement leading to the increased cell death and presumed glial progenitor inflammatory response, we used a dual in situ labeling technique that incorporated the MitoTracker Deep Red dye and MitoPY1 fluorescein dye [15] to simultaneously track mitochondrial function and oxidative stress

Summary

Introduction

Down syndrome (DS) arises from a triplication of genes on chromosome 21 (HSA21) and is characterized by neurological complications including mental retardation and early onset Alzheimer’s disease (AD) [1]. DS brains show prolongation in the cell cycle length of neural progenitors [2,3], as well as increased oxidative stress and mitochondrial dysfunction within neurons [3,4,5]. These findings would suggest that both abnormalities in proliferation and progressive neuronal loss through apoptosis contribute to the developmental neuropathology in DS. Studies using DS human neural progenitors (HNPs) have proposed several mechanisms underlying the loss in neuronal numbers in DS brain. Expression profiling of 18 week gestational age (W GA) DS HNPs followed by in vitro studies are able to demonstrate constitutive overexpression of HSA21 associated S100B, leading to increased reactive oxygen species (ROS) formation, activation of stress response kinases, and cell death [6]

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Results

Conclusion