Asaba Tomoki, Hamano Sayuri, Nanmo Ayaka, Seo Jieun, Kageyama Tatsuto, Fukuda Junji
Faculty of Engineering, Yokohama National University, 79-5 Tokiwadai, Hodogaya-ku, Yokohama, Kanagawa, 240-8501, Japan.
Regen Ther. 2025 Jun 26;30:259-267. doi: 10.1016/j.reth.2025.06.013. eCollection 2025 Dec.
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.
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 Aβ 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.
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.
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.
神经炎症是阿尔茨海默病（AD）发病机制的关键因素，小胶质细胞对β淀粉样蛋白（Aβ）的清除受损与疾病进展密切相关。催产素（OXT）是一种下丘脑神经肽，最近有报道称其对小胶质细胞具有抗炎作用；然而，其在人脑中的治疗潜力仍不清楚。
我们从诱导多能干细胞（iPSC）生成人脑海绵体（hCO），以模拟早期AD样病理。通过施加3μM Aβ 48小时诱导Aβ毒性。通过免疫组织化学、RT-qPCR、钙成像和多电极阵列（MEA）记录评估OXT的保护作用。通过免疫染色和TREM2的基因表达分析评估小胶质细胞在Aβ清除中的作用。
Aβ暴露导致Aβ在hCO外层大量沉积，同时伴有神经活动受抑制和凋亡信号增加。OXT预处理以浓度依赖的方式减轻了Aβ沉积和caspase-3介导的凋亡。OXT还恢复了MEA测量的钙振荡和神经网络活动。值得注意的是，OXT增强了小胶质细胞向Aβ沉积物的募集，并上调了小胶质细胞吞噬作用的关键调节因子TREM2的表达。Iba1阳性小胶质细胞上催产素受体（OXTR）的共表达表明OXT直接调节小胶质细胞活化和Aβ清除。
OXT通过保护人皮质类器官的神经元活性并促进小胶质细胞介导的Aβ清除，对其具有神经保护作用。本研究为OXT针对AD患者神经炎症和Aβ病理的治疗潜力提供了新的见解。
