Zinc Is Involved In The Pathogenesis Of Alzheimer’s Disease Through Regulating The Metabolic Balance Of Cyclooxygenase-2

Alzheimer’s disease(Alzheimer’s disease,AD)is a neurodegenerative disease characterized by progressive dementia,the clinical manifestations are memory progressive loss,cognitive impairment,mental and behavioral disorders,personality disorders.The main neuropathological features of AD include:① A large number of senile plaques composed of beta amyloid(β-amyloid protein,Aβ)and denatured cell debris outside the cell;② Neurogenic fibrous tangles(Neurofibrillary tangles,NFTs)formed by hyperphosphorylated tau protein accumulation in the denatured neurons.It is found that the pathogenesis of AD is related to zinc metabolism disorder in the brain and neuroimmune inflammation characterized by microglia excessive activation producing a large number of inflammatory factors.Zinc ions concentration increased significantly in the cortex,hippocampus and amygdala in advanced AD patients,in addition to inducing Aβ deposition,zinc ions can also induce tau protein overphosphorylation.In addition,cyclooxygenase-2(Cyclooxygenase-2,COX-2)plays a special role in the inflammatory response,and plays an important role in the pathogenesis of AD,it may be an important factor affecting the susceptibility of AD.Therefore,to further clarify the relationship between zinc ion metabolic disorder and AD inflammatory response,and the effects of these factors on the neuropathological changes of AD,In this study,the brain slices of AD patients at different onset and transgenic mice expressing P301S tau mutant genes were used as experimental models in vivo,the mouse source neuron cell N2a was used as an in vitro model,detected the effects of zinc ions on the expression of inflammatory factors TNF-α(Tumor necrosis factor-α,TNF-α),COX-2 and their metabolites by intraventricular injection and experimental methods of molecular biology,and analyzed the correlation between zinc ion and tau protein phosphorylation.The results showed that high concentration of zinc ions could increase TNF-α and COX-2 expression through the zinc transporter ZnT3(Zinc transporter 3,ZnT3),high expression of COX-2 and its downstream metabolites PGI3 and PGF2α stimulate tau protein phosphorylation at Ser202 and Ser400/Thr403/Ser404 through PI3-K/AKT,ERK1/2 and JNK/c-Jun pathway,lead to the occurrence and development of AD.In addition,NS398 is a specific inhibitor of COX-2,intraventricular injection NS398 treatment in tau transgenic mice,we found that tau protein phosphorylation levels were significantly lower in tau treatment group mouse brains compared with the control group and AD model group,and NS398 therapy could significantly improve the cognitive ability of mice.In vitro experiments further confirmed that NS398 could reduce zinc ions or TNF-α induced tau protein phosphorylation.Morphological studies have further confirmed that ZnT3 was not only localized on the synaptic vesicle membrane of axon terminals in zinc neurons,but also expressed in microglia and astrocytes,It is interesting to find that by fluorescent confocal staining,ZnT3 was colocated with COX-2 in microglia.In addition,high levels of zinc ions could upregulate COX-2 expression through the zinc transporter ZnT3 in microglia.High expression of COX-2 through its downstream metabolites PGF2α activated microglia to secrete inflammatory factor TNF-α by PI3-K/AKT and ERK1/2 pathway,finally,TNF-α effected on astrocytes,and induced astrocytes activation,these processes led to a vicious cycle of inflammation in AD.In summary,zinc ions are closely related to inflammatory reaction in the brain of AD.The relationship between zinc ions and inflammatory reaction played a vital role in the development of the AD.During the occurrence of AD,zinc ions play an important regulatory role in inflammatory factors or COX-2 and downstream metabolites expression,affect tau protein phosphorylation and microglia activation.This study systematically revealed the mechanism of zinc ions,COX-2 and inflammatory factors involved in the development of AD,It provides a full theoretical basis for the establishment of a new strategy for the regulation of brain zinc homeostasis and anti inflammation as the treatment of neurodegenerative diseases such as AD.