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. Mechanismly, 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.

中文翻译：

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MC-LR 暴露后自噬通量阻断导致阿尔茨海默病样变化的不良结局途径


微囊藻毒素 （MCs） 污染是一个关系到人类健康的世界性环境问题。微囊藻毒素-亮氨酸-精氨酸 （MC-LR） 是蓝藻产生的最常见 MC 类型，可进入大脑并对神经系统造成损害。迄今为止，尚不清楚 MC-LR 诱导的神经毒性的机制。淀粉样蛋白 β （Aβ） 沉积物是阿尔茨海默病 （AD） 的标志。在这项研究中，我们揭示了环境相关剂量 （1、7.5、15 μg/L） 的 MC-LR 暴露可以促进小鼠大脑中 Aβ 的积累。从机制上讲，我们首先发现 Aβ 积累与 MC-LR 暴露后神经元自噬通量阻断和溶酶体功能障碍引起的异常 Aβ 降解密切相关。此外，本研究建立了面向 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，这被认为是分子起始事件 （MIE）。此外，在 MC-LR 暴露后观察到自噬异常。自噬体-溶酶体融合受阻和溶酶体功能破坏是 MC-LR 暴露后的关键事件 （KEs），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）。这项研究提供了有关 MC-LR 神经毒性的新信息，并为理解环境化学物质诱导的神经退行性疾病的潜在机制提供了新的见解，这对公共卫生具有深远的影响。