Dataset Information

S100B and APP promote a gliocentric shift and impaired neurogenesis in Down syndrome neural progenitors.

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.

SUBMITTER: Lu J

PROVIDER: S-EPMC3133657 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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S100B and APP promote a gliocentric shift and impaired neurogenesis in Down syndrome neural progenitors.

Lu Jie J Esposito Giuseppe G Scuderi Caterina C Steardo Luca L Delli-Bovi Laurent C LC Hecht Jonathan L JL Dickinson Bryan C BC Chang Christopher J CJ Mori Takashi T Sheen Volney V

PloS one 20110711 7

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 ...[more]

PMID: 21779383

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Project description:BACKGROUND: Pathological angiogenesis represents a critical issue in the progression of many diseases. Down syndrome is postulated to be a systemic anti-angiogenesis disease model, possibly due to increased expression of anti-angiogenic regulators on chromosome 21. The aim of our study was to elucidate some features of circulating endothelial progenitor cells in the context of this syndrome. METHODS: Circulating endothelial progenitors of Down syndrome affected individuals were isolated, in vitro cultured and analyzed by confocal and transmission electron microscopy. ELISA was performed to measure SDF-1? plasma levels in Down syndrome and euploid individuals. Moreover, qRT-PCR was used to quantify expression levels of CXCL12 gene and of its receptor in progenitor cells. The functional impairment of Down progenitors was evaluated through their susceptibility to hydroperoxide-induced oxidative stress with BODIPY assay and the major vulnerability to the infection with human pathogens. The differential expression of crucial genes in Down progenitor cells was evaluated by microarray analysis. RESULTS: We detected a marked decrease of progenitors' number in young Down individuals compared to euploid, cell size increase and some major detrimental morphological changes. Moreover, Down syndrome patients also exhibited decreased SDF-1? plasma levels and their progenitors had a reduced expression of SDF-1? encoding gene and of its membrane receptor. We further demonstrated that their progenitor cells are more susceptible to hydroperoxide-induced oxidative stress and infection with Bartonella henselae. Further, we observed that most of the differentially expressed genes belong to angiogenesis, immune response and inflammation pathways, and that infected progenitors with trisomy 21 have a more pronounced perturbation of immune response genes than infected euploid cells. CONCLUSIONS: Our data provide evidences for a reduced number and altered morphology of endothelial progenitor cells in Down syndrome, also showing the higher susceptibility to oxidative stress and to pathogen infection compared to euploid cells, thereby confirming the angiogenesis and immune response deficit observed in Down syndrome individuals.

Dataset Information

S100B and APP promote a gliocentric shift and impaired neurogenesis in Down syndrome neural progenitors.

Publications

S100B and APP promote a gliocentric shift and impaired neurogenesis in Down syndrome neural progenitors.

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