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miR-128-3p is involved in aluminum-induced cognitive impairment by regulating the Sirt1-Keap1/Nrf2 pathway
Huan Li1, Yan Liu2, Xiangmeng Wang3
1Department of Occupational Health, School of Public Health, Jining Medical University, Jining, China; Department of Occupational Health, School of Public Health, Shanxi Medical University, Taiyuan, China.
Abstract:
Aluminum (Al) is a common neurotoxicant in the environment, but the molecular mechanism of its toxic effects is still unclear. Studies have shown that aluminum exposure causes an increase in neuronal apoptosis. The aim of this study was to investigate the mechanism and signaling pathway of neuronal apoptosis induced by aluminum exposure. The rat model was established by intraperitoneal injection of maltol aluminum for 90 days. The results showed that the escape latency of the three groups exposed to maltol aluminum was higher than that of the control group on the 3rd, 4th and 5th days of the positioning cruise experiment (P < 0.05). On the 6th day of the space exploration experiment, compared with the control group(6.00 ± 0.71,15.33 ± 1.08) and the low-dose group(5.08 ± 1.69,13.67 ± 1.09), the number of times that the high-dose group crossed the platform(2.25 ± 0.76) and the platform quadrant(7.58 ± 1.43) was significantly reduced (P < 0.01). The relative expression levels of Sirt1 and Nrf2 in hippocampal tissues of all groups decreased gradually with increasing maltol aluminum exposure dose the relative expression levels of Sirt1 and Nrf2 in high-dose group (0.261 ± 0.094,0.325 ± 0.108) were significantly lower than those in control group (1.018 ± 0.222,1.009 ± 0.156)(P < 0.05). The relative expression level of Keap1 increased gradually with increasing maltol aluminum exposure dose (P < 0.05). The relative expression level of miR-128-3p in the high-dose group(1.520 ± 0.280) was significantly higher than that in the control group(1.000 ± 0.420) (P < 0.05). The content of GSH-Px in the hippocampus of rats decreased with increasing dose. ROS levels gradually increased. We speculated that subchronic aluminum exposure may lead to the activation of miR-128-3p in rat hippocampus of rats, thereby inhibiting the Sirt1-Keap1/Nrf2 pathway so that the Sirt1-Keap1/Nrf2 pathway could not be activated to exert antioxidant capacity, resulting in an imbalance in the antioxidant system of rats and the apoptosis of neurons, which caused reduced cognitive impairment in rats.
Insights
Aluminum exposure impairs cognitive function by inducing neuronal apoptosis. This study reveals that aluminum activates miR-128-3p, inhibiting the Sirt1-Keap1/Nrf2 pathway, disrupting antioxidant capacity, and causing cognitive deficits.
Area of Science:
- Neuroscience
- Toxicology
- Molecular Biology
Background:
- Aluminum (Al) is an environmental neurotoxicant with unclear molecular mechanisms of toxicity.
- Aluminum exposure is linked to increased neuronal apoptosis and cognitive impairment.
Purpose of the Study:
- To investigate the molecular mechanism and signaling pathway of aluminum-induced neuronal apoptosis.
- To elucidate the role of the Sirt1-Keap1/Nrf2 pathway and miR-128-3p in aluminum neurotoxicity.
Main Methods:
- A rat model was established via intraperitoneal injection of maltol aluminum for 90 days.
- Behavioral tests (positioning cruise, space exploration) assessed cognitive function.
- Hippocampal tissues were analyzed for the expression of Sirt1, Nrf2, Keap1, and miR-128-3p.
- Oxidative stress markers (GSH-Px, ROS) were measured.
Main Results:
- Aluminum exposure significantly increased escape latency and reduced platform crossings, indicating cognitive impairment.
- Expression of Sirt1 and Nrf2 decreased, while Keap1 and miR-128-3p expression increased with higher aluminum doses.
- Reduced glutathione peroxidase (GSH-Px) and elevated reactive oxygen species (ROS) levels were observed.
- These changes suggest inhibition of the Sirt1-Keap1/Nrf2 antioxidant pathway.
Conclusions:
- Subchronic aluminum exposure activates miR-128-3p in the rat hippocampus.
- This activation inhibits the Sirt1-Keap1/Nrf2 pathway, impairing antioxidant capacity and leading to neuronal apoptosis.
- The disruption of the antioxidant system contributes to cognitive deficits observed in aluminum-exposed rats.
