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Down Syndrome iPSC-Derived Astrocytes Impair Neuronal Synaptogenesis and the mTOR Pathway In Vitro

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Abstract

Several methods have been used to study the neuropathogenesis of Down syndrome (DS), such as mouse aneuploidies, post mortem human brains, and in vitro cell culture of neural progenitor cells. More recently, induced pluripotent stem cell (iPSC) technology has offered new approaches in investigation, providing a valuable tool for studying specific cell types affected by DS, especially neurons and astrocytes. Here, we investigated the role of astrocytes in DS developmental disease and the impact of the astrocyte secretome in neuron mTOR signaling and synapse formation using iPSC derived from DS and wild-type (WT) subjects. We demonstrated for the first time that DS neurons derived from hiPSC recapitulate the hyperactivation of the Akt/mTOR axis observed in DS brains and that DS astrocytes may play a key role in this dysfunction. Our results bear out that 21 trisomy in astrocytes contributes to neuronal abnormalities in addition to cell autonomous dysfunctions caused by 21 trisomy in neurons. Further research in this direction will likely yield additional insights, thereby improving our understanding of DS and potentially facilitating the development of new therapeutic approaches.

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Funding

This study was supported by grants from Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP; Centros de Pesquisa, Inovação e Difusão (CEPID), number 2013/08028-1). Bruno H. S. Araujo, Ernesto Goulart, and Luiz C. J. Caires are fellows of FAPESP (2014/08049-1; 2015/14821-1; 2017/16283-2); Carolini Kaid and Camila M. Musso are fellows of Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES; 1469761; 1470032); Janaina S. de Souza is a fellow of Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq; 18952-12-7).

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Authors and Affiliations

  1. Department of Neurosurgery and Neurology, Laboratory of Neuroscience, Universidade Federal de São Paulo (UNIFESP/EPM), São Paulo, São Paulo, Brazil

    Bruno H. S. Araujo & Esper A. Cavalheiro

  2. Brazilian Biosciences National Laboratory (LNBio), Brazilian Center for Research in Energy and Materials (CNPEM), Rua Giuseppe Máximo Scolfaro, no. 10.000, Campinas, São Paulo, 13083-970, Brazil

    Bruno H. S. Araujo

  3. Department of Genetics and Evolutionary Biology, Human Genome and Stem Cell Research Center, Institute of Biosciences, Universidade de São Paulo (USP), São Paulo, São Paulo, Brazil

    Carolini Kaid, Ernesto Goulart, Luiz C. J. Caires, Camila M. Musso, Mayana Zatz & Oswaldo K. Okamoto

  4. Department of Medicine, Laboratory of Endocrinology and Translational Medicine, Universidade Federal de São Paulo (UNIFESP/EPM), São Paulo, São Paulo, Brazil

    Janaina S. De Souza

  5. Hospital Israelita Albert Einstein (HIAE), São Paulo, São Paulo, Brazil

    Sérgio Gomes da Silva

  6. Universidade de Mogi das Cruzes, Mogi das Cruzes, São Paulo, Brazil

    Sérgio Gomes da Silva

  7. São Leopoldo Mandic Institute and Research Center, Campinas, São Paulo, Brazil

    Laila B. Torres

  8. Experimental Multiuser Laboratory (LEM), Graduate Program in Health Sciences (PPGCS), School of Medicine, Pontifícia Universidade Católica do Paraná (PUCPR), Curitiba, Paraná, 80215-901, Brazil

    Adriano Ferrasa

  9. Department of Informatics (DEINFO), Universidade Estadual de Ponta Grossa (UEPG), Ponta Grossa, Paraná, 84030-900, Brazil

    Adriano Ferrasa & Roberto Herai

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  1. Bruno H. S. Araujo
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  2. Carolini Kaid
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  3. Janaina S. De Souza
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  6. Luiz C. J. Caires
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Correspondence to Bruno H. S. Araujo.

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Araujo, B.H.S., Kaid, C., De Souza, J.S. et al. Down Syndrome iPSC-Derived Astrocytes Impair Neuronal Synaptogenesis and the mTOR Pathway In Vitro. Mol Neurobiol 55, 5962–5975 (2018). https://doi.org/10.1007/s12035-017-0818-6

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