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Reduced neural progenitor cell (NPC) proliferation, delayed neurogenesis, impaired cortical lamination and altered cell fate specification are thought to contribute to cognitive impairments in DS individuals. The molecular mechanisms underlying these deficits are not fully understood. Notably, Amyloid precursor protein (APP), located on human chromosome 21 (HSA21), has been extensively implicated in these processes. Mouse models only partially recapitulate DS phenotypes due to genetic, developmental, and species-specific differences. Recent advances in induced pluripotent stem cell (iPSC) derived 3D cortical organoids allow for the study of DS cortical development in a human model system. Here, we show that normalizing APP gene copy number in DS cortical organoids ameliorated deficits in NPC proliferation, neuronal differentiation, and transcriptional programs. Our results demonstrate the value of cortical organoids in uncovering gene-specific roles in DS pathogenesis and identify APP as a promising target for addressing early neurodevelopmental impairments.<\/jats:p>","DOI":"10.1101\/2025.07.26.666926","type":"posted-content","created":{"date-parts":[[2025,7,27]],"date-time":"2025-07-27T11:20:10Z","timestamp":1753615210000},"source":"Crossref","is-referenced-by-count":0,"title":["Amyloid precursor protein mediates deficits in corticogenesis in Down syndrome cortical organoids"],"prefix":"10.64898","author":[{"given":"Karen","family":"Rakowiecki","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deepika","family":"Patel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis Aponte","family":"Cofresi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Orly","family":"Lazarov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025072904200685000_2025.07.26.666926v1.1","doi-asserted-by":"publisher","DOI":"10.1002\/BDR2.1589"},{"key":"2025072904200685000_2025.07.26.666926v1.2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/dds052"},{"key":"2025072904200685000_2025.07.26.666926v1.3","doi-asserted-by":"crossref","unstructured":"Baburamani, A. 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