Ma Yuhan, Xu Dihui, Gan Yibin, Chen Zining, Chen Yabing, Han Xiaodong
State Key Laboratory of Analytical Chemistry for Life Science, Division of Anatomy and Histo-Embryology, Medical School, Nanjing University, Nanjing, Jiangsu, 210093, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu, 210093, China.
State Key Laboratory of Analytical Chemistry for Life Science, Division of Anatomy and Histo-Embryology, Medical School, Nanjing University, Nanjing, Jiangsu, 210093, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, Jiangsu, 210093, China.
Environ Pollut. 2025 Jan 1;364(Pt 1):125322. doi: 10.1016/j.envpol.2024.125322. Epub 2024 Nov 15.
Microcystins (MCs) pollution is a worldwide environmental issue concerning about human health. Microcystin-leucine-arginine (MC-LR), the most common type of MCs produced by cyanobacteria, could enter the brain and bring about damage to the nervous system. Up to date, it is not clear about the mechanism of MC-LR-induced neurotoxicity. Amyloid-β (Aβ) deposits are hallmark of Alzheimer's disease (AD). In this study, we revealed that MC-LR exposure at environment-related doses (1, 7.5, 15 μg/L) could promote Aβ accumulation in mouse brain. Mechanically, we firstly found that Aβ accumulation is closely associated with abnormal Aβ degradation due to autophagy flux blockade and lysosome dysfunctions in neurons after MC-LR exposure. Moreover, an adverse outcome pathway (AOP) framework oriented to neurotoxicity of MC-LR was conducted in this study. MC-LR inhibited the activity of protein phosphatase 2A (PP2A) in neurons, which is regarded as a molecular initiating event (MIE). In addition, the abnormalities in autophagy were observed after MC-LR exposure. The hindered autophagosome-lysosome fusion and disrupted lysosomal function were key events (KEs) after MC-LR exposure, which contributed to proteostasis dysregulation, ultimately leading to Aβ abnormal degradation and learning deficits as adverse outcomes (AO) of neurotoxicity. This study provided novel information about MC-LR neurotoxicity and new insights into understanding the mechanisms underlying the environmental chemicals-induced neurodegeneration diseases, which has deep implications for public health.
微囊藻毒素（MCs）污染是一个关乎人类健康的全球性环境问题。微囊藻毒素 - 亮氨酸 - 精氨酸（MC - LR）是蓝藻产生的最常见的微囊藻毒素类型，可进入大脑并对神经系统造成损害。截至目前，MC - LR诱导神经毒性的机制尚不清楚。淀粉样β蛋白（Aβ）沉积是阿尔茨海默病（AD）的标志。在本研究中，我们发现环境相关剂量（1、7.5、15μg/L）的MC - LR暴露可促进小鼠大脑中Aβ的积累。从机制上讲，我们首先发现Aβ积累与MC - LR暴露后神经元中自噬通量阻断和溶酶体功能障碍导致的Aβ异常降解密切相关。此外，本研究构建了一个针对MC - LR神经毒性的不良结局途径（AOP）框架。MC - LR抑制神经元中蛋白磷酸酶2A（PP2A）的活性，这被视为一个分子起始事件（MIE）。此外，MC - LR暴露后观察到自噬异常。MC - LR暴露后自噬体 - 溶酶体融合受阻和溶酶体功能破坏是关键事件（KEs），这导致蛋白质稳态失调，最终导致Aβ异常降解和学习缺陷，作为神经毒性的不良结局（AO）。本研究提供了关于MC - LR神经毒性的新信息，并为理解环境化学物质诱导神经退行性疾病的潜在机制提供了新见解，这对公共卫生具有深远意义。
