Chronic MC-LR exposure promoted A beta and p-tau accumulation via regulating Akt/GSK-3 beta signal pathway
Chronic MC-LR exposure promoted A beta and p-tau accumulation via regulating Akt/GSK-3 beta signal pathway
复制标题
慢性 MC-LR 暴露通过调节 Akt/GSK-3 β 信号通路促进 A beta 和 p-tau 积累
DOI：
10.1016/j.scitotenv.2021.148732
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发表时间：
2021
影响因子：
9.8
通讯作者：
Xiaodong Han
中科院分区：
文献类型：
--
作者：
Yuhan Ma;Jing Wang;Dihui Xu;Yabing Chen;Xiaodong Han
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，导致学习和记忆障碍。然而，目前对其相关的分子机制仍缺乏清晰的认识。在本研究中，我们观察了不同浓度(1，7.5，15和30βg/β)的MC-LR慢性暴露180天后，小鼠海马区和大脑皮层Ser396和Thr205位点A-μ积聚和tau蛋白过度磷酸化(p-tau)的变化。阿尔茨海默病的特点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和tau过度磷酸化的产生。此外，MC-LR还可促进体内和体外ADAM家族成员BACE1和PS1的表达增加，而降低其基因表达，从而促进A-β的产生。此外，我们还发现Akt/GSK-3β信号通路介导了Atau和p-tau的积聚，导致了类阿尔茨海默病的改变。此外，暴露于MC-LR的小鼠的小胶质细胞被激活。在体外也发现炎性细胞因子被激活以释放。总之，这项研究可以为MC-LR诱导的神经毒性提供线索，从而为阿尔茨海默病的环境风险提供见解。
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 bothin vivoandin 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 releasein 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.