Munni Yeasmin Akter, Tran Khoa Nguyen, Jeon Seon-Min, Hwang Meeyul, Yoon Jong-Won, Song Young-Ha, Oh Tae Woo, Gum Sang Il, Yang In-Jun
Department of Physiology, Dongguk University College of Korean Medicine, Gyeongju, Republic of Korea.
QBGEN Inc., Gyeongsan, Republic of Korea.
Front Pharmacol. 2025 Aug 21;16:1598030. doi: 10.3389/fphar.2025.1598030. eCollection 2025.
The development of new drugs for Alzheimer's disease (AD) remains a major challenge due to the disorder's complex and multifactorial nature. 2'-Fucosyllactose (2'-FL), a human milk oligosaccharide, has demonstrated promising neuroprotective properties. However, its effects on AD-related cognitive decline are not yet fully understood. This study aimed to investigate the therapeutic potential of 2'-FL in an aging mouse model of AD and to explore the underlying mechanisms involved.
5xFAD transgenic mice were treated with 2'-FL and assessed for cognitive function using the Morris water maze and Y-maze tests. Immunohistochemical staining was used to evaluate amyloid-beta (Aβ) and phosphorylated tau (p-tau) levels in brain tissue samples. Blood samples were analyzed to determine circulating cytokine levels. Additionally, BV2 microglial cells and primary hippocampal neurons (PHNs) were used to investigate the effects of 2'-FL on neuroinflammation, oxidative stress, and synaptic plasticity.
2'-FL (300-1,200 mg/kg, oral) improved cognitive performance in 5xFAD mice by shortening escape latency in the water maze and restoring alternation behavior in the Y-maze test. It significantly reduced Aβ plaque load in the hippocampus and cortex but did not significantly affect tau hyperphosphorylation. Furthermore, 2'-FL lowered plasma tumor necrosis factor (TNF)-α and interleukin (IL)-6 levels. In BV2 cells, it suppressed d-galactose-induced neuroinflammation by downregulating TNF-α and IL-6, and nuclear factor-κB signaling. In PHNs, 2'-FL reduced oxidative stress, restored mitochondrial function, and limited DNA damage. Additionally, it counteracted d-galactose-induced synaptic deficits by promoting neurite outgrowth, enhancing synaptic vesicle recycling, and upregulating the synaptic markers brain-derived neurotrophic factor, postsynaptic density protein-95, and synaptic vesicle protein 2.
2'-FL improved cognitive performance in 5xFAD mice, reduced Aβ plaque deposition and pro-inflammatory cytokine levels , and mitigated oxidative stress and synaptic dysfunction in cellular models. These findings indicate that 2'-FL modulates multiple pathological features relevant to AD in preclinical models.
由于阿尔茨海默病（AD）具有复杂的多因素性质，开发治疗该疾病的新药仍然是一项重大挑战。2'-岩藻糖基乳糖（2'-FL）是一种人乳寡糖，已显示出有前景的神经保护特性。然而，其对AD相关认知衰退的影响尚未完全了解。本研究旨在探讨2'-FL在AD衰老小鼠模型中的治疗潜力，并探索其中涉及的潜在机制。
用2'-FL处理5xFAD转基因小鼠，并使用莫里斯水迷宫和Y迷宫试验评估其认知功能。免疫组织化学染色用于评估脑组织样本中β-淀粉样蛋白（Aβ）和磷酸化tau蛋白（p-tau）的水平。分析血液样本以确定循环细胞因子水平。此外，使用BV2小胶质细胞和原代海马神经元（PHN）来研究2'-FL对神经炎症、氧化应激和突触可塑性的影响。
2'-FL（300 - 1200毫克/千克，口服）通过缩短水迷宫中的逃避潜伏期和恢复Y迷宫试验中的交替行为，改善了5xFAD小鼠的认知表现。它显著降低了海马体和皮质中的Aβ斑块负荷，但对tau蛋白过度磷酸化没有显著影响。此外，2'-FL降低了血浆肿瘤坏死因子（TNF）-α和白细胞介素（IL）-6水平。在BV2细胞中，它通过下调TNF-α、IL-6和核因子-κB信号通路，抑制了d-半乳糖诱导的神经炎症。在PHN中，2'-FL减少了氧化应激，恢复了线粒体功能，并限制了DNA损伤。此外，它通过促进神经突生长、增强突触小泡循环和上调突触标记物脑源性神经营养因子、突触后密度蛋白-95和突触小泡蛋白2，抵消了d-半乳糖诱导的突触缺陷。
2'-FL改善了5xFAD小鼠的认知表现，减少了Aβ斑块沉积和促炎细胞因子水平，并减轻了细胞模型中的氧化应激和突触功能障碍。这些发现表明，2'-FL在临床前模型中调节了与AD相关的多种病理特征。
