Chen Qiqi, Wang Zhiqiu, Guo Wei, Xue Aiqin, Bian Guohui, Guo Xinhua, Lu Shiya, Zeng Pinli, Li Hao, Zhu Xizhi, Huang Yan, Cen Xiaobo, Bu Qian
Molecular Toxicology Key Laboratory of Sichuan Provincial Education Office, Institute of Systems Epidemiology, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, China.
National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy, Collaborative Innovation Center of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China.
Antioxidants (Basel). 2025 May 7;14(5):553. doi: 10.3390/antiox14050553.
Alzheimer's disease (AD), a prevalent neurodegenerative disorder in the elderly, poses significant humanistic and economic burdens worldwide. Previously, we identified Trp-Leu-Pro (WLP), a novel antioxidant peptide derived from the sea squirt (); however, its effects on AD remained unexplored. In this study, we developed a rapid and efficient method to generate AD cerebral organoids with consistent quality using okadaic acid (OKA) exposure. This study aimed to evaluate the protective effects of WLP on OKA-induced AD pathology in cerebral organoids and elucidate its underlying mechanisms. Our results demonstrated that cerebral organoids exposed to 25 nM OKA successfully recapitulated hallmark AD pathologies, including amyloid-beta (Aβ) plaque deposits, neurofibrillary tangles (NFTs) formed by hyperphosphorylated tau proteins, and neuronal loss. WLP treatment significantly enhanced cell viability, increased the proportion of neuronal progenitor cells, and reduced Aβ plaques and NFTs in OKA-induced cerebral organoids. Furthermore, transcriptomic analysis revealed that the neuroprotective effects of WLP are primarily mediated through the regulation of synapse-related and oxidative stress pathways. These findings highlight the potential of WLP as a promising nutraceutical candidate for AD prevention.
阿尔茨海默病（AD）是老年人中一种常见的神经退行性疾病，在全球范围内造成了巨大的人文和经济负担。此前，我们鉴定出一种来自海鞘的新型抗氧化肽色氨酸-亮氨酸-脯氨酸（WLP）；然而，其对AD的影响尚未得到探索。在本研究中，我们开发了一种快速有效的方法，通过暴露于冈田酸（OKA）来生成质量一致的AD脑类器官。本研究旨在评估WLP对OKA诱导的脑类器官中AD病理的保护作用，并阐明其潜在机制。我们的结果表明，暴露于25 nM OKA的脑类器官成功再现了AD的标志性病理特征，包括β淀粉样蛋白（Aβ）斑块沉积、由过度磷酸化的tau蛋白形成的神经原纤维缠结（NFTs）以及神经元丢失。WLP处理显著提高了细胞活力，增加了神经元祖细胞的比例，并减少了OKA诱导的脑类器官中的Aβ斑块和NFTs。此外，转录组分析表明，WLP的神经保护作用主要通过调节突触相关和氧化应激途径来介导。这些发现突出了WLP作为一种有前景的用于预防AD的营养保健品候选物的潜力。
