APP/PS1 Gene-Environmental Cadmium Interaction Aggravates the Progression of Alzheimer’s Disease in Mice via the Blood-Brain Barrier, Amyloid-β, and Inflammation

Article type: Research Article

Authors: Liu, Jieyi^{a; 1} | Xie, Yirong^{a; 1} | Lu, Yao^{b; 1} | Zhao, Zhiqiang^c | Zhuang, Zhixiong^d | Yang, Linqing^d | Huang, Haiyan^d | Li, Hongya^a | Mao, Zhiyi^a | Pi, Shurong^a | Chen, Fubin^a | He, Yun^{a; *}

Affiliations: [a] Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou, Guangdong, China | [b] Office of Academic Affairs, Southern Medical University, Guangzhou, Guangdong, China | [c] Department of Toxicology, Guangdong Province Hospital for Occupational Disease Prevention and Treatment, Guangzhou, Guangdong, China | [d] Shenzhen Center for Disease Control and Prevention, Shenzhen, China

Correspondence: [*] Correspondence to: Yun He, Department of Toxicology, School of Public Health, Sun Yat-sen University, 74 Zhongshan 2nd Road, Guangzhou, Guangdong 510080, China. Tel.: +0086 20 87332321; E-mail: heyun7@mail.sysu.edu.cn.

Note: [1] These authors contributed equally to this work.

Abstract: Background:There is limited information about gene-environment interaction on the occurrence and the progression of Alzheimer’s disease. Objective:To explore the effect of environmental low-dose cadmium (Cd) exposure on the progress of Alzheimer’s disease and the underlining mechanism. Methods:We administered 1 mg/L, 10 mg/L cadmium chloride (treated groups), and water (control group) to C57BL/6J and APP/PS1 mice through drinking water, from one week before mating, until the offspring were sacrificed at 6 months of age. The behaviors, Cd level, blood-brain barrier (BBB) leakage, Aβ1-42 deposition, and inflammation expression were evaluated in these mice. Results:Mice of both genotypes had similar blood Cd levels after exposure to the same dose of Cd. The toxic effects of Cd on the two genotypes differed little in terms of neuronal histomorphology and BBB permeability. Cd caused a series of pathological morphological changes in the mouse brains and more fluorescent dye leakage at higher doses. Furthermore, the APP/PS1 mice had more severe damage than the C57BL/6J mice, based on the following five criteria. They were increasing anxiety-like behavior and chaos movement, spatial reference memory damage, Aβ plaque deposition in mouse brains, increasing microglia expression in the brain, and IL-6 higher expression in the cortex and in the serum. Conclusion:Low-dose Cd exposure for 6 months increases Aβ plaque deposition and BBB permeability, exacerbates inflammatory responses, and activates microglia, in APP/PS1 mice. APP/PS1 gene-environmental Cd interaction aggravates the progression of Alzheimer’s disease in mice.

Keywords: Alzheimer’s disease, APP/PS1 gene, blood-brain barrier, cadmium, gene-environment interaction, inflammatory response

DOI: 10.3233/JAD-221205

Journal: Journal of Alzheimer's Disease, vol. 94, no. 1, pp. 115-136, 2023