Human iPSC-derived cerebral organoids reveal oxytocin-mediated protection against amyloid-β pathology
Introduction: Neuroinflammation is a key contributor to the pathogenesis of Alzheimer's disease (AD), and impaired clearance of amyloid-β (Aβ) by microglia is closely associated with disease progression. Oxytocin (OXT), a hypothalamic neuropeptide, has recently been reported to exert anti-infla...
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| Language: | English |
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Elsevier
2025-12-01
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| Series: | Regenerative Therapy |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352320425001464 |
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| author | Tomoki Asaba Sayuri Hamano Ayaka Nanmo Jieun Seo Tatsuto Kageyama Junji Fukuda |
| author_facet | Tomoki Asaba Sayuri Hamano Ayaka Nanmo Jieun Seo Tatsuto Kageyama Junji Fukuda |
| author_sort | Tomoki Asaba |
| collection | DOAJ |
| description | Introduction: Neuroinflammation is a key contributor to the pathogenesis of Alzheimer's disease (AD), and impaired clearance of amyloid-β (Aβ) by microglia is closely associated with disease progression. Oxytocin (OXT), a hypothalamic neuropeptide, has recently been reported to exert anti-inflammatory effects on microglia; however, its therapeutic potential in the human brain remains unclear. Methods: We generated human cerebral organoids (hCOs) from induced pluripotent stem cells (iPSCs) to model early AD-like pathology. Aβ toxicity was induced by applying 3 μM Aβ1–42 for 48 h. The protective effects of OXT were evaluated through immunohistochemistry, RT-qPCR, calcium imaging, and multielectrode array (MEA) recordings. The involvement of microglia in Aβ clearance was assessed by immunostaining and gene expression analysis of TREM2. Results: Aβ exposure led to significant deposition of Aβ in the outer layers of hCOs, accompanied by suppressed neural activity and increased apoptotic signaling. Pretreatment with OXT attenuated Aβ deposition and caspase-3-mediated apoptosis in a concentration-dependent manner. OXT also restored calcium oscillations and neuronal network activity as measured by MEA. Notably, OXT enhanced the recruitment of microglia to Aβ deposits and upregulated the expression of TREM2, a key regulator of microglial phagocytosis. Co-expression of oxytocin receptors (OXTR) on Iba1-positive microglia suggests that OXT directly modulates microglial activation and Aβ clearance. Conclusions: OXT has neuroprotective effects on human cortical organoids by preserving their neuronal activity and promoting microglial-mediated Aβ clearance. This study provides novel insights into the therapeutic potential of OXT for targeting neuroinflammation and Aβ pathology in patients with AD. |
| format | Article |
| id | doaj-art-d2bd27110b364690bf49dc47591cd82f |
| institution | Kabale University |
| issn | 2352-3204 |
| language | English |
| publishDate | 2025-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Regenerative Therapy |
| spelling | doaj-art-d2bd27110b364690bf49dc47591cd82f2025-08-20T03:24:13ZengElsevierRegenerative Therapy2352-32042025-12-013025926710.1016/j.reth.2025.06.013Human iPSC-derived cerebral organoids reveal oxytocin-mediated protection against amyloid-β pathologyTomoki Asaba0Sayuri Hamano1Ayaka Nanmo2Jieun Seo3Tatsuto Kageyama4Junji Fukuda5Faculty of Engineering, Yokohama National University, 79-5 Tokiwadai, Hodogaya-ku, Yokohama, Kanagawa, 240-8501, JapanFaculty of Engineering, Yokohama National University, 79-5 Tokiwadai, Hodogaya-ku, Yokohama, Kanagawa, 240-8501, JapanFaculty of Engineering, Yokohama National University, 79-5 Tokiwadai, Hodogaya-ku, Yokohama, Kanagawa, 240-8501, JapanFaculty of Engineering, Yokohama National University, 79-5 Tokiwadai, Hodogaya-ku, Yokohama, Kanagawa, 240-8501, JapanFaculty of Engineering, Yokohama National University, 79-5 Tokiwadai, Hodogaya-ku, Yokohama, Kanagawa, 240-8501, JapanCorresponding author.; Faculty of Engineering, Yokohama National University, 79-5 Tokiwadai, Hodogaya-ku, Yokohama, Kanagawa, 240-8501, JapanIntroduction: Neuroinflammation is a key contributor to the pathogenesis of Alzheimer's disease (AD), and impaired clearance of amyloid-β (Aβ) by microglia is closely associated with disease progression. Oxytocin (OXT), a hypothalamic neuropeptide, has recently been reported to exert anti-inflammatory effects on microglia; however, its therapeutic potential in the human brain remains unclear. Methods: We generated human cerebral organoids (hCOs) from induced pluripotent stem cells (iPSCs) to model early AD-like pathology. Aβ toxicity was induced by applying 3 μM Aβ1–42 for 48 h. The protective effects of OXT were evaluated through immunohistochemistry, RT-qPCR, calcium imaging, and multielectrode array (MEA) recordings. The involvement of microglia in Aβ clearance was assessed by immunostaining and gene expression analysis of TREM2. Results: Aβ exposure led to significant deposition of Aβ in the outer layers of hCOs, accompanied by suppressed neural activity and increased apoptotic signaling. Pretreatment with OXT attenuated Aβ deposition and caspase-3-mediated apoptosis in a concentration-dependent manner. OXT also restored calcium oscillations and neuronal network activity as measured by MEA. Notably, OXT enhanced the recruitment of microglia to Aβ deposits and upregulated the expression of TREM2, a key regulator of microglial phagocytosis. Co-expression of oxytocin receptors (OXTR) on Iba1-positive microglia suggests that OXT directly modulates microglial activation and Aβ clearance. Conclusions: OXT has neuroprotective effects on human cortical organoids by preserving their neuronal activity and promoting microglial-mediated Aβ clearance. This study provides novel insights into the therapeutic potential of OXT for targeting neuroinflammation and Aβ pathology in patients with AD.http://www.sciencedirect.com/science/article/pii/S2352320425001464Alzheimer's diseaseAmyloid-betaCerebral organoidsMicrogliaOxytocinAnti-inflammatory signaling |
| spellingShingle | Tomoki Asaba Sayuri Hamano Ayaka Nanmo Jieun Seo Tatsuto Kageyama Junji Fukuda Human iPSC-derived cerebral organoids reveal oxytocin-mediated protection against amyloid-β pathology Regenerative Therapy Alzheimer's disease Amyloid-beta Cerebral organoids Microglia Oxytocin Anti-inflammatory signaling |
| title | Human iPSC-derived cerebral organoids reveal oxytocin-mediated protection against amyloid-β pathology |
| title_full | Human iPSC-derived cerebral organoids reveal oxytocin-mediated protection against amyloid-β pathology |
| title_fullStr | Human iPSC-derived cerebral organoids reveal oxytocin-mediated protection against amyloid-β pathology |
| title_full_unstemmed | Human iPSC-derived cerebral organoids reveal oxytocin-mediated protection against amyloid-β pathology |
| title_short | Human iPSC-derived cerebral organoids reveal oxytocin-mediated protection against amyloid-β pathology |
| title_sort | human ipsc derived cerebral organoids reveal oxytocin mediated protection against amyloid β pathology |
| topic | Alzheimer's disease Amyloid-beta Cerebral organoids Microglia Oxytocin Anti-inflammatory signaling |
| url | http://www.sciencedirect.com/science/article/pii/S2352320425001464 |
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