Morita Satoshi, Kondo Takayuki, Tokuda Hisanori, Kaneda Yoshihisa, Izumo Takayuki, Nakao Yoshihiro, Inoue Haruhisa
iPSC-based Drug Discovery and Development Team, RIKEN BioResource Research Center (BRC), Kyoto, Japan.
Institute for Science of Life, Suntory Wellness Ltd., Kyoto, Japan.
iScience. 2025 May 12;28(6):112557. doi: 10.1016/j.isci.2025.112557. eCollection 2025 Jun 20.
The effects and mechanisms of polyunsaturated fatty acids (PUFAs) including docosahexaenoic acid (DHA) and arachidonic acid (ARA) contained in the lipid membrane of neurons in the production of amyloid β (Aβ), a pathogenic molecule in Alzheimer's disease (AD), remain unclear. In this study, we cultured human cortical neurons differentiated from induced pluripotent stem cells (iPSCs) under conditions of PUFA deficiency being progressively alleviated. Under PUFA-deficient conditions, increasing the total PUFA composition ratio in the lipid membrane enhanced membrane fluidity and reduced Aβ production. Furthermore, in conditions where the overall PUFA deficiency was resolved, altering the specific ratios of DHA and ARA promoted the synchronous activity and morphological complexity of neuronal cells while maintaining consistent membrane fluidity. These findings demonstrate that the overall PUFA composition in the lipid membrane as well as the specific ratios of DHA and ARA within the total PUFAs regulate neuronal function and pathophysiology.
神经元脂质膜中含有的多不饱和脂肪酸（PUFA），包括二十二碳六烯酸（DHA）和花生四烯酸（ARA），在阿尔茨海默病（AD）致病分子β淀粉样蛋白（Aβ）产生中的作用及机制尚不清楚。在本研究中，我们在逐步缓解PUFA缺乏的条件下，培养了由诱导多能干细胞（iPSC）分化而来的人皮质神经元。在PUFA缺乏的条件下，提高脂质膜中总PUFA组成比例可增强膜流动性并减少Aβ产生。此外，在整体PUFA缺乏得到解决的条件下，改变DHA和ARA的特定比例可促进神经元细胞的同步活动和形态复杂性，同时保持膜流动性一致。这些发现表明，脂质膜中的整体PUFA组成以及总PUFAs中DHA和ARA的特定比例调节着神经元功能和病理生理学。
