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Background <p>Down syndrome (DS), or trisomy 21 (T21), resulting from an extra copy of chromosome 21, occurs in 1 in 700–1,000 live births. Neuroinflammation is increasingly recognized as a critical contributor to DS neuropathology, although its underlying drivers remain unclear.</p> Methods <p>In this study, we analyzed available single-nucleus RNA sequencing (snRNAseq) data from <i>postmortem</i> cortical brains of individuals with DS and controls aged 36 years or younger, focusing specifically on astrocyte-enriched clusters. This analysis revealed significant alterations in complement system gene sets. To further investigate these findings, we employed a human in vitro model using astrocytes differentiated from urine-derived induced pluripotent stem cells (iPSCs) obtained from individuals with DS (T21-iPSCs). To our knowledge, this is the first study to evaluate both gene expression and protein levels of secreted complement components in T21-iPSC-derived astrocytes.</p> Results <p>snRNAseq re-analyzes identified an upregulation of complement system components, including <i>C1R</i>, <i>C1S</i>, <i>C2</i>, <i>C4A</i>, <i>C4B</i>, <i>C5</i>, <i>C5AR1</i>, <i>C6</i>, <i>C8</i>, <i>CD59</i>, <i>CFI</i>, and <i>FCN2</i>, and of glutamate transporters <i>SLC1A3</i> (<i>EAAT1/GLAST-1</i>) and <i>SLC1A2</i> (<i>EAAT2/GLT-1</i>) in DS astrocytes. Results from the in vitro model revealed distinct phenotypic changes in T21-iPSC-derived astrocytes, including enlarged cell and nuclear sizes, and enhanced glutamate uptake. Elevated levels of <i>C5aR1</i> and <i>MASP1</i> transcripts, as well as increased C4 protein secretion in culture supernatants, suggest dysregulation of the complement system in DS.</p> Conclusions <p>These findings highlight the potential contribution of astrocyte-driven complement signaling to DS neuropathogenesis. While further validation is needed, this work points to a candidate pathway that may serve as a target for future therapeutic investigation to improve the quality of life for individuals with DS.</p>

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Complement pathway dysregulation and astrocyte alterations in Down syndrome: evidence from postmortem brain tissue and iPSC-derived astrocytes

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月5日

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  • André Luíz Teles e Silva,
  • Pedro Henrique Prado de Oliveira,
  • Bruno Yukio Yokota-Moreno,
  • Jéssica da Silva Fausto,
  • Jonatan Peña Avila,
  • Helder I. Nakaya,
  • Andréa Laurato Sertié,
  • Bruna Lancia Zampieri

摘要

Background

Down syndrome (DS), or trisomy 21 (T21), resulting from an extra copy of chromosome 21, occurs in 1 in 700–1,000 live births. Neuroinflammation is increasingly recognized as a critical contributor to DS neuropathology, although its underlying drivers remain unclear.

Methods

In this study, we analyzed available single-nucleus RNA sequencing (snRNAseq) data from postmortem cortical brains of individuals with DS and controls aged 36 years or younger, focusing specifically on astrocyte-enriched clusters. This analysis revealed significant alterations in complement system gene sets. To further investigate these findings, we employed a human in vitro model using astrocytes differentiated from urine-derived induced pluripotent stem cells (iPSCs) obtained from individuals with DS (T21-iPSCs). To our knowledge, this is the first study to evaluate both gene expression and protein levels of secreted complement components in T21-iPSC-derived astrocytes.

Results

snRNAseq re-analyzes identified an upregulation of complement system components, including C1R, C1S, C2, C4A, C4B, C5, C5AR1, C6, C8, CD59, CFI, and FCN2, and of glutamate transporters SLC1A3 (EAAT1/GLAST-1) and SLC1A2 (EAAT2/GLT-1) in DS astrocytes. Results from the in vitro model revealed distinct phenotypic changes in T21-iPSC-derived astrocytes, including enlarged cell and nuclear sizes, and enhanced glutamate uptake. Elevated levels of C5aR1 and MASP1 transcripts, as well as increased C4 protein secretion in culture supernatants, suggest dysregulation of the complement system in DS.

Conclusions

These findings highlight the potential contribution of astrocyte-driven complement signaling to DS neuropathogenesis. While further validation is needed, this work points to a candidate pathway that may serve as a target for future therapeutic investigation to improve the quality of life for individuals with DS.