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

Author(s):Show less -

Araujo, Bruno H. S. ^{[1, 2]} ; Kaid, Carolini ^[3] ; De Souza, Janaina S. ^[4] ; da Silva, Sergio Gomes ^{[5, 6]} ; Goulart, Ernesto ^[3] ; Caires, Luiz C. J. ^[3] ; Musso, Camila M. ^[3] ; Torres, Laila B. ^[7] ; Ferrasa, Adriano ^{[8, 9]} ; Herai, Roberto ^[9] ; Zatz, Mayana ^[3] ; Okamoto, Oswaldo K. ^[3] ; Cavalheiro, Esper A. ^[1]

Affiliation

^[1] Univ Fed Sao Paulo, UNIFESP EPM, Lab Neurosci, Dept Neurosurg & Neurol, Sao Paulo, SP - Brazil

^[2] Brazilian Ctr Res Energy & Mat CNPEM, Brazilian Biosci Natl Lab LNBio, Rua Giuseppe Maximo Scolfaro 10-000, BR-13083970 Campinas, SP - Brazil

^[3] Univ Sao Paulo, Inst Biosci, Human Genome & Stem Cell Res Ctr, Dept Genet & Evolutionary Biol, Sao Paulo, SP - Brazil

^[4] Univ Fed Sao Paulo, UNIFESP EPM, Lab Endocrinol & Translat Med, Dept Med, Sao Paulo, SP - Brazil

^[5] Univ Mogi das Cruzes, Mogi Das Cruzes, SP - Brazil

^[6] HIAE, Sao Paulo, SP - Brazil

^[7] Sao Leopoldo Mandic Inst & Res Ctr, Campinas, SP - Brazil

^[8] Pontificia Univ Catolica Parana PUCPR, Sch Med, Grad Program Hlth Sci PPGCS, Expt Multiuser Lab LEM, BR-80215901 Curitiba, Parana - Brazil

^[9] Univ Estadual Ponta Grossa, Dept Informat DEINFO, BR-84030900 Ponta Grossa, Parana - Brazil

• Document type: Journal article
• Source: Molecular Neurobiology; v. 55, n. 7, p. 5962-5975, JUL 2018.
• Web of Science Citations: 6

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. (AU)

• FAPESP's process: 17/16283-2 - Development of tissue bioengineering techniques for the functional reconstruction of ex vivo iPSC cell livers
• Grantee: Luiz Carlos de Caires Júnior
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 15/14821-1 - Development of functional hepatic by-pass using iPSCs-derived cells
• Grantee: Ernesto da Silveira Goulart Guimarães
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 14/08049-1 - The role of astrocytes in the synaptic plasticity of neurons derived from induced pluripotent stem cells from Down Syndrome patients
• Grantee: Bruno Henrique Silva Araujo Torres
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 13/08028-1 - CEGH-CEL - Human Genome and Stem Cell Research Center
• Grantee: Mayana Zatz
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC