Evidence for Apoptosis in the Fetal Down Syndrome Brain

Seidl, Rainer; Bidmon, Bettina; Bajo, M.; Yoo, Byon C.; Cairns, Nigel J.; LaCasse, Eric C.; Lübec, Gert

doi:10.1177/088307380101600610

Cited by 33 publications

(29 citation statements)

References 32 publications

(14 reference statements)

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“…Intriguingly, our in vivo transplantation study recapitulates the effects of DS astroglia on neurogenesis and the effects of minocycline. A previous study in human tissue61 demonstrates the enhanced neuronal cell death in the human fetal DS brain (35 weeks’ gestation). We do not observe significant neuronal cell death in the animals that received Tri-DS3 astroglia transplant.…”

Section: Discussionmentioning

confidence: 83%

Role of astroglia in Down’s syndrome revealed by patient-derived human-induced pluripotent stem cells

et al. 2014

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Down’s syndrome (DS), caused by trisomy of human chromosome 21, is the most common genetic cause of intellectual disability. Here we use induced pluripotent stem cells (iPSCs) derived from DS patients to identify a role for astrocytes in DS pathogenesis. DS astroglia exhibit higher levels of reactive oxygen species and lower levels of synaptogenic molecules. Astrocyte-conditioned medium collected from DS astroglia causes toxicity to neurons, and fails to promote neuronal ion channel maturation and synapse formation. Transplantation studies show that DS astroglia do not promote neurogenesis of endogenous neural stem cells in vivo. We also observed abnormal gene expression profiles from DS astroglia. Finally, we show that the FDA-approved antibiotic drug, minocycline, partially corrects the pathological phenotypes of DS astroglia by specifically modulating the expression of S100B, GFAP, inducible nitric oxide synthase, and thrombospondins 1 and 2 in DS astroglia. Our studies shed light on the pathogenesis and possible treatment of DS by targeting astrocytes with a clinically available drug.

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Section: Discussionmentioning

confidence: 83%

Role of astroglia in Down’s syndrome revealed by patient-derived human-induced pluripotent stem cells

et al. 2014

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“…Studies of Down syndrome and the corresponding trisomy 16 mouse model have reported large increases in cell death with a significant reduction in cortical mass (48)(49)(50)(51)(52). Similar parallels can be drawn between the ATRX-deficient mice and the human disorder.…”

Section: Discussionmentioning

confidence: 66%

The chromatin-remodeling protein ATRX is critical for neuronal survival during corticogenesis

Bérubé¹,

Mangelsdorf²,

Jagla³

et al. 2005

J. Clin. Invest.

177

158

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Mutations in genes encoding chromatin-remodeling proteins, such as the ATRX gene, underlie a number of genetic disorders including several X-linked mental retardation syndromes; however, the role of these proteins in normal CNS development is unknown. Here, we used a conditional gene-targeting approach to inactivate Atrx, specifically in the forebrain of mice. Loss of ATRX protein caused widespread hypocellularity in the neocortex and hippocampus and a pronounced reduction in forebrain size. Neuronal "birthdating" confirmed that fewer neurons reached the superficial cortical layers, despite normal progenitor cell proliferation. The loss of cortical mass resulted from a 12-fold increase in neuronal apoptosis during early stages of corticogenesis in the mutant animals. Moreover, cortical progenitors isolated from Atrx-null mice undergo enhanced apoptosis upon differentiation. Taken together, our results indicate that ATRX is a critical mediator of cell survival during early neuronal differentiation. Thus, increased neuronal loss may contribute to the severe mental retardation observed in human patients.

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“…Down syndrome is one example of such defects in which, due to the increased apoptosis in early development, brain cell number is decreased, and adult individuals usually exhibit an Alzheimer's like dementia (Seidl et al 2001). In addition to genetic causes, perturbations in developmental apoptosis may be due to neurotoxicant exposure.…”

Section: Discussionmentioning

confidence: 99%

Maternal Oral Consumption of Morphine Increases Bax/Bcl-2 Ratio and Caspase 3 Activity During Early Neural System Development in Rat Embryos

et al. 2009

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Maternal morphine consumption has been shown to result in physical and neurobehavioral defects in fetus and offspring, but the underlying molecular mechanisms of these defects remain unclear. Regarding the critical role of apoptosis in normal development of central nervous system, the present study was designed to investigate the effect of intrauterine morphine exposure on programmed cell death of neuroblasts during the early development of neural system. Pregnant Wistar rats received morphine sulfate through drinking water at the concentration of 0.01 mg/ml (20 ml water per day for each rat) from the first day of gestation to the time of sampling. Control groups received tap water. Control and morphine-treated pregnant rats, each in five separated groups, were killed on gestational days 9.5 to 13.5, and the embryos were taken out, fixed, and embedded in paraffin. Immunohistochemical assay was used to reveal the protein expression of Bax, Bcl2, and the activation of caspase 3. The results showed a significant increase in Bax immunoreactivity in all of the mentioned embryonic days (E9.5 to E13.5) and a significant decrease in Bcl-2 immunoreactivity at days E10.5 and E12.5 in morphine-treated groups compared with control. Data analysis revealed that Bax/Bcl2 ratio was increased in all of the morphine-exposed groups. Consistent with these results, immunostaining of cleaved caspase 3 showed a significant increase at days E11.5 to E13.5. These findings suggest that morphine exposure during the first embryonic days may enhance the susceptibility of neuroblasts to apoptosis by upregulating the ratio of Bax to Bcl-2 protein expression and increasing downstream caspase-3 activity. The increased probability of neuroblast apoptosis may be the cause of morphine-induced defects in the central nervous system development and its structural and neurobehavioral consequences.

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Evidence for Apoptosis in the Fetal Down Syndrome Brain

Cited by 33 publications

References 32 publications

Role of astroglia in Down’s syndrome revealed by patient-derived human-induced pluripotent stem cells

Role of astroglia in Down’s syndrome revealed by patient-derived human-induced pluripotent stem cells

The chromatin-remodeling protein ATRX is critical for neuronal survival during corticogenesis

Maternal Oral Consumption of Morphine Increases Bax/Bcl-2 Ratio and Caspase 3 Activity During Early Neural System Development in Rat Embryos

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