Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing 210093, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing 210093, China.
Immunology and Reproduction Biology Laboratory & State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing 210093, China; Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing 210093, China.
Sci Total Environ. 2021 Nov 10;794:148732. doi: 10.1016/j.scitotenv.2021.148732. Epub 2021 Jun 29.
It has been reported that microcystin-leucine-arginine (MC-LR) can enter into the brain and demonstrate neurotoxicity resulting in learning and memory deficits. While, there is still a lack of clear understanding of the related molecular mechanisms. In this study, we observed β-amyloid (Aβ) accumulation and tau hyperphosphorylation (p-tau) at sites of Ser396 and Thr205 in mouse hippocampus and cortex, Alzheimer's disease (AD) like changes, after chronic exposure to MC-LR at different concentrations (1, 7.5, 15 and 30 μg/L) for 180 days. The hallmarks of AD are characterized by senile plaques and neurofibrillary tangles (NFT), with associated loss of neurons, resulting in cognitive impairment and dementia. Similarly, the production of Aβ and tau hyperphosphorylation was also detected in HT-22 cells treated with MC-LR. In addition, MC-LR promoted increased expressions of BACE1 and PS1, but reduced mRNA expressions of ADAM family members both in vivo and in vitro, promoting the Aβ production. Moreover, we identified Akt/GSK-3β signal pathway mediated the Aβ and p-tau accumulation, bringing about Alzheimer's disease-like changes. Furthermore, microglial cells were activated in those mice exposed to MC-LR. Inflammatory cytokines were also found being activated to release in vitro. In conclusion, this study could provide a clue for MC-LR-induced neurotoxicity, which gave insights into the environmental risks of Alzheimer's disease.
据报道，微囊藻毒素-亮氨酸-精氨酸（MC-LR）可以进入大脑并表现出神经毒性，导致学习和记忆缺陷。然而，目前对于相关的分子机制仍缺乏清晰的认识。在这项研究中，我们观察到慢性暴露于不同浓度（1、7.5、15 和 30μg/L）MC-LR 180 天后，小鼠海马和皮质中β-淀粉样蛋白（Aβ）的积累和tau 的过度磷酸化（p-tau）在丝氨酸 396 和苏氨酸 205 位点，以及阿尔茨海默病（AD）样变化。AD 的特征是老年斑和神经原纤维缠结（NFT），伴随着神经元的丢失，导致认知障碍和痴呆。同样，在 MC-LR 处理的 HT-22 细胞中也检测到 Aβ的产生和 tau 的过度磷酸化。此外，MC-LR 促进了 BACE1 和 PS1 的表达增加，但降低了体内和体外 ADAM 家族成员的 mRNA 表达，促进了 Aβ的产生。此外，我们确定 Akt/GSK-3β信号通路介导了 Aβ和 p-tau 的积累，导致了阿尔茨海默病样变化。此外，暴露于 MC-LR 的小鼠中微胶质细胞被激活。体外也发现炎症细胞因子被激活释放。总之，这项研究为 MC-LR 诱导的神经毒性提供了线索，为阿尔茨海默病的环境风险提供了新的认识。
