Astrocytes of the murine model for Down Syndrome Ts65Dn display reduced intracellular ionic zinc

Ballestín, Raúl; Blasco-Ibáñez, José Miguel; Crespo, Carlos; Nácher, Juan; López-Hidalgo, Rosa; Gilabert-Juan, Javier; Moltó, Dolores; Varea, Emilio

doi:10.1016/j.neuint.2014.05.013

Cited by 12 publications

(11 citation statements)

References 38 publications

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“…Additionally, App is increased at the protein secretion level (FC 2.17, p<0.0001). Increased levels of Mt3 and Efemp1 proteins have been reported in astrocytes in DS patients, and we detect increased levels of both in DS ACM (Mt3 FC 5.96, p<0.0001; Efemp1 FC 5.62, p=0.0001) 42,49 . Pathway analysis of proteins increased in DS ACM identified the amyloid secretase pathway in Alzheimer's disease, integrin signaling pathway, and regulation of IGF transport and uptake by Igfbps ( Figure 3k).…”

Section: Identification Of Altered Protein Secretion and Gene Expresssupporting

confidence: 67%

Aberrant astrocyte protein secretion contributes to altered neuronal development in diverse disorders

Caldwell

Diedrich

Shokhirev

et al. 2020

Preprint

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Astrocytes negatively impact neuronal development in many neurodevelopmental disorders (NDs), however how they do this, and if mechanisms are shared across disorders, is not known.We developed an in vitro system to ask how astrocyte protein secretion and gene expression change in three genetic NDs. We identified disorder specific changes, and changes common to all disorders. ND astrocytes increase release of Igfbp2, a secreted inhibitor of IGF. IGF rescues neuronal deficits in many NDs, and we found blocking Igfbp2 partially rescues inhibitory effects of Rett Syndrome astrocytes, suggesting increased astrocyte Igfbp2 contributes to decreased IGF signaling in NDs. We identified increased BMP signaling in ND astrocytes is upstream of protein secretion changes, including Igfbp2, and blocking BMP signaling in Fragile X Syndrome astrocytes reverses inhibitory effects on neurite outgrowth. We provide a resource of astrocyte secreted proteins in health and NDs, and identify novel targets for intervention in diverse NDs.

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Section: Identification Of Altered Protein Secretion and Gene Expresssupporting

confidence: 67%

Aberrant astrocyte protein secretion contributes to altered neuronal development in diverse disorders

Caldwell

Diedrich

Shokhirev

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Growing evidence suggests that astrocytes substantially contribute to neurological and psychiatric disorders by affecting neuronal function (Cao et al, 2013; Di Giorgio et al, 2008; Marchetto et al, 2008; Molofsky et al, 2012; Tong et al, 2014). Indeed, astrocytes have been implicated in multiple rodent studies as playing an important role in DS (Ballestin et al, 2014; Bambrick et al, 2003). A number of genes involved in DS, including THBS1 and APP, have been shown to be expressed in astrocytes and have been implicated in Alzheimer’s disease (Garcia et al, 2010; Torres et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Aberrant Calcium Signaling in Astrocytes Inhibits Neuronal Excitability in a Human Down Syndrome Stem Cell Model

et al. 2018

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Down syndrome (DS) is a genetic disorder that causes cognitive impairment. The staggering effects associated with an extra copy of human chromosome 21 (HSA21) complicates mechanistic understanding of DS pathophysiology. We examined the neuron-astrocyte interplay in a fully recapitulated HSA21 trisomy cellular model differentiated from DS-patient-derived induced pluripotent stem cells (iPSCs). By combining calcium imaging with genetic approaches, we discovered the functional defects of DS astroglia and their effects on neuronal excitability. Compared with control isogenic astroglia, DS astroglia exhibited more-frequent spontaneous calcium fluctuations, which reduced the excitability of co-cultured neurons. Furthermore, suppressed neuronal activity could be rescued by abolishing astrocytic spontaneous calcium activity either chemically by blocking adenosine-mediated signaling or genetically by knockdown of inositol triphosphate (IP) receptors or S100B, a calcium binding protein coded on HSA21. Our results suggest a mechanism by which DS alters the function of astrocytes, which subsequently disturbs neuronal excitability.

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“…Similar to the abnormality in astrocytes described in both young and adult DS patients [122,123], enhanced astrogliosis was observed in Ts65Dn mice [120]. In primary astrocyte cultures from Ts65Dn mice, altered astrocyte proliferation and Ca 2+ activity as well as reduced intracellular free zinc have been described [124,125]. Considering the limitation of animal models to recapitulate the triplication of HSA21 in DS patients, human fetal and postmortem tissues are used.…”

Section: Down Syndromementioning

confidence: 84%

Modeling Neurodevelopmental and Neuropsychiatric Diseases with Astrocytes Derived from Human-Induced Pluripotent Stem Cells

Ren

Dunaevsky

2021

IJMS

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Accumulating studies demonstrate the morphological and functional diversity of astrocytes, a subtype of glial cells in the central nervous system. Animal models are instrumental in advancing our understanding of the role of astrocytes in brain development and their contribution to neurological disease; however, substantial interspecies differences exist between rodent and human astrocytes, underscoring the importance of studying human astrocytes. Human pluripotent stem cell differentiation approaches allow the study of patient-specific astrocytes in the etiology of neurological disorders. In this review, we summarize the structural and functional properties of astrocytes, including the unique features of human astrocytes; demonstrate the necessity of the stem cell platform; and discuss how this platform has been applied to the research of neurodevelopmental and neuropsychiatric diseases.

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Astrocytes of the murine model for Down Syndrome Ts65Dn display reduced intracellular ionic zinc

Cited by 12 publications

References 38 publications

Aberrant astrocyte protein secretion contributes to altered neuronal development in diverse disorders

Aberrant astrocyte protein secretion contributes to altered neuronal development in diverse disorders

Aberrant Calcium Signaling in Astrocytes Inhibits Neuronal Excitability in a Human Down Syndrome Stem Cell Model

Modeling Neurodevelopmental and Neuropsychiatric Diseases with Astrocytes Derived from Human-Induced Pluripotent Stem Cells

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