Mechanisms Of Chlorogenic Acids Against Aluminum Neurotoxicity

With the widespread application of aluminum in the food industry,clinical and medical area,daily life and other fields,more and more people are facing the hazard caused by aluminum exposure.The most sensitive target for aluminum exposure is the central nervous system,and the prolonged exposure to aluminum can lead to neurodegenerative diseases,but the associated pathogenesis has not yet been clarified.In this paper,cell experiments and animal experiments were used to study the mechanism of nervous system damage caused by aluminum and the effect and mechanism of chlorogenic acid on the removal of aluminum toxicity.(1)The effects of chlorogenic acid on the cognitive impairment in mice induced by aluminum exposure were systematically explored in this study by taking the ICR mice as the study subjects.The results showed that chlorogenic acid could effectively prevent cognitive impairment in mice induced by aluminum exposure.In Morris Water Maze Experiment,the latency of chlorogenic acid-intervened mice(100 mg/kg)was shortened by 49.7%compared to that of the aluminum-treated mice;while in the Step-Down Test,the latency of chlorogenic acid-intervened mice(100 mg/kg)was shortened by 13.8%compared to that of the aluminum-treated mice.The experiments of metabolic and accumulation showed that chlorogenic acid could promote the excretion of aluminum in the feces and reduce the accumulation of aluminum in the hippocampus of mice.The observation on the hippocampal tissue structure showed that chlorogenic acid was able to effectively improve the structural damage of neurons in hippocampus,weaken the neuron karyopyknosis and mitochondria swelling to restore the synaptic structure.Immunological results showed that the intervention of chlorogenic acid could effectively activate the Nfr2-Keapl oxidative stress signaling pathway in mice’s neuron cells and reduce their cell damage caused by aluminum exposure.(2)The effects of coffee chlorogenic acid on neuronal cell oxidative stress induced by aluminum exposure were systematically investigated in this study by taking the primary hippocampal neurons of rats and ICR mice as the study object.The results showed that chlorogenic acid could significantly reduce the damage of oxidative stress caused by aluminum exposure.Compared with the aluminum treatment group,chlorogenic acid intervention was able to reduce the generation of free radicals,MDA content,mitochondrial membrane damage,and enhance antioxidant enzyme activity,creatine kinase activity and ATP synthesis.Immunological analysis indicated that chlorogenic acid intervention was able to effectively activate the nuclear factor-E2-related factor 2 Kelch-like ECH associated protein 1(Nrf2-Keap1)signaling pathway and the downstream phase Ⅱ enzyme’s expression,so as to reduce oxidative damage caused by exposure to aluminum.(3)In this study,the molecular mechanism of aluminum-induced Alzheimer’s disease was studied in detail on the basis of replicating the model of nerve injury caused by aluminum exposure.The study showed that the aluminum ions got a specific binding with the 14-3-3ζ after entering into the cell,reduced the affinity of the chaperone protein 14-3-3ζ and vascular bundles connexin tau,then the released tau protein accumulated in the synapse after being excessively phosphorylated,thus forming the nerve fiber tangles.The study separated the whole protein of brain tissue by Native-PAGE and utilized the fluorescence of binding Al3+ and 8-hydroxyquinoline together to realize the visualization of pro-Al protein,and the results showed that the brain-type creatine kinase and 14-3-3ζ protein possess a high pro-Al activity.It was found by the immunological method that aluminum exposure could increase the expression of phosphorylated tau protein and the formation of nerve fiber tangles in rat hippocampus(dentate gyrus and hippocampal gyrus 3),and reduce the interaction between 14-3-3ζ and tau protein.(4)In order to further evaluate the protective mechanism of chlorogenic acid against aluminum exposure to develop towards Alzheimer’s disease,this study used 100 mg/kg and 50μm chlorogenic acid to intervene in Wistar rats and their primary hippocampal neuron cells.The results showed that chlorogenic acid can compete with Al3+ in cells,reduce the interaction between Al3+ and 14-3-3ζprotein,so as to increase the protective effect of chaperone protein 14-3-3ζ and tau protein and prevent the excessive phosphorylation of tau protein.In addition,it was found that chlorogenic acid can significantly reduce the formation of nerve fiber tangles in cells,which might be due to the combination of chlorogenic acid with some structural domains of tau and the subsequent neutralization of the latter’s phosphoric acid epitopes and avoidance of excessive phosphorylation of tau protein.This paper systematically discussed the biological effects of aluminum exposure on nerve cell injury,and studied the protective effect of chlorogenic acid on nerve injury induced by aluminum exposure and its mechanism.The results showed that chlorogenic acid can activate Nrf2-Keapl signaling pathway to protect nerve cells from oxidative stress damage caused by aluminum exposure,and chlorogenic acid can compete with Al3+,regulate the interaction between 14-3-3ζ and tau protein,so as to prevent the formation of nerve fiber tangles.This study is able to provide a new idea and suggestion for finding the target sites suitable for preventing and treating the nerve injury caused by aluminum exposure and the discovery of new anti-Al drugs.