Lead aggravates Alzheimer's disease pathology via mitochondrial copper accumulation regulated by COX17

作者：Huang, Dingbang; Chen, Lixuan; Ji, Qiuyi; Xiang, Yang; Zhou, Qin; Chen, Kaiju; Zhang, Xiaoshun; Zou, Fei; Zhang, Xingmei; Zhao, Zaihua; Wang, Tao; Zheng, Gang^*; Meng, Xiaojing^*

来源：Redox Biology, 2024, 69: 102990.

DOI：10.1016/j.redox.2023.102990

• Pb
• Microglia
• Alzheimer's disease
• Mitochondrial copper
• Mitochondrial ROS

Alzheimer's disease (AD) is a common neurodegenerative disease that is associated with multiple environmental risk factors, including heavy metals. Lead (Pb) is a heavy metal contaminant, which is closely related to the incidence of AD. However, the research on the role of microglia in Pb-induced AD-like pathology is limited. To determine the mechanism by which Pb exposure aggravates AD progression and the role of microglial activation, we exposed APP/PS1 mice and A beta 1-42-treated BV-2 cells to Pb. Our results suggested that chronic Pb exposure exacerbated learning and memory impairments in APP/PS1 mice. Pb exposure increased the activation of microglia in the hippocampus of APP/PS1 mice, which was associated with increased deposition of A beta 1-42, and induced hippocampal neuron damage. Pb exposure upregulated copper transporter 1 (CTR1) and downregulated copper P-type ATPase transporter (ATP7A) in the hippocampus of APP/PS1 mice and A beta 1-42-treated BV-2 cells. Moreover, Pb enhanced mitochondrial translocation of the mitochondrial copper transporter COX17, leading to an increase in mitochondrial copper concentration and mitochondrial damage. This could be reversed by copperchelating agents or by inhibiting the mitochondrial translocation of COX17. The increased mitochondrial copper concentration caused by increased mitochondrial translocation of COX17 after Pb exposure may be related to the enhanced mitochondrial import pathway of AIF/CHCHD4. These results indicate that Pb induces the activation of microglia by increasing the concentration of copper in the mitochondria of microglia, and microglia release inflammatory factors to promote neuroinflammation, thus aggravating the pathology of AD. The present study provides new ideas for the prevention of Pb-induced AD.

• 单位
  南方医科大学; 中国人民解放军第四军医大学