Molecular and cellular processes disrupted in the early postnatal Down syndrome prefrontal cortex

• 成果类型: Article
• 署名作者: Risgaard, Ryan D.; Hanthanan Arachchilage, Kalpana; Knaack, Sara A.; Hosseini, Masoumeh; Chen, Rachel J.; Kumarage, Pubudu; Schmidt, Danielle K.; Huang, Xiang; Sheng, Jie; Wang, Carlos J.; Giusti, Elisa; Liu, Shuang; Zhang, Su-Chun; Wang, Daifeng; Bhattacharyya, Anita; Sousa, Andre M. M.
• 署名单位: University of Wisconsin System; University of Wisconsin Madison; University of Wisconsin System; University of Wisconsin Madison; Sanford Burnham Prebys Medical Discovery Institute; University of Wisconsin System; University of Wisconsin Madison; University of Wisconsin System; University of Wisconsin Madison; University of Wisconsin System; University of Wisconsin Madison
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8075; 1095-9203
• DOI: 10.1126/science.aea1549
• 发表日期: 2026-04-23
• 页码: eaea1549
• 关键词: R/BIOCONDUCTOR PACKAGE; alzheimers-disease; young-adults; HUMAN-FETUS; individuals; microglia; TRIPLICATION; adolescents; dysfunction; annotation

摘要

Down syndrome is a genetic condition that causes intellectual disability and is characterized by early-onset delays in motor, cognitive, and language development. The molecular mechanisms underlying these neurodevelopmental impairments remain poorly understood. We used single-nucleus multiomic sequencing to simultaneously profile gene expression and chromatin accessibility in the Down syndrome prefrontal cortex during early postnatal development, a critical period for synaptogenesis, neural maturation, and developmental neuroimmune interactions. Our findings reveal widespread dysregulation of chromatin accessibility and gene expression, with deficits spanning metabolic and synaptic pathways, oligodendrocyte lineage progression, and a pronounced neuroinflammatory signature. We present a molecular atlas of Down syndrome neuropathology at a critical stage of brain development, highlighting convergent neurodevelopmental and neurodegenerative pathways and informing potential targeted therapies for Down syndrome-associated neuroinflammation.