Department of Neurosurgery and Neurology, Laboratory of Neuroscience, Universidade Federal de São Paulo (UNIFESP/EPM), São Paulo, São Paulo, Brazil.
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.
Mol Neurobiol. 2018 Jul;55(7):5962-5975. doi: 10.1007/s12035-017-0818-6. Epub 2017 Nov 11.
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.
已经有几种方法被用于研究唐氏综合征（DS）的神经发病机制，例如小鼠染色体非整倍性、尸检人脑和神经祖细胞的体外培养。最近，诱导多能干细胞（iPSC）技术为研究提供了新的方法，为研究受 DS 影响的特定细胞类型（尤其是神经元和星形胶质细胞）提供了有价值的工具。在这里，我们使用来自 DS 和野生型（WT）个体的 iPSC 研究了星形胶质细胞在 DS 发育性疾病中的作用以及星形胶质细胞分泌组对神经元 mTOR 信号和突触形成的影响。我们首次证明，源自 hiPSC 的 DS 神经元重现了在 DS 大脑中观察到的 Akt/mTOR 轴的过度激活，并且 DS 星形胶质细胞可能在这种功能障碍中发挥关键作用。我们的结果表明，除了神经元中的 21 三体引起的细胞自主功能障碍之外，星形胶质细胞中的 21 三体也会导致神经元异常。朝着这个方向的进一步研究可能会提供更多的见解，从而加深我们对 DS 的理解，并可能促进新的治疗方法的开发。
