Studay On The Mechanism Of Action Of Danggui Shaoyao San On Alzheimer Disease In Mice Based On TOLL-like Receptor 4

Alzheimer'sdisease?AD?isaneurodegenerativedisorder characterized by cognitive impairment and progressive memory impairment.Its main pathological features are the deposition of extracellular amyloid??A??to form senile plaques and the hyperphosphorylation of intracellular tau protein to form neurofibrillary tangles and a decrease in the number of cerebral cortical neurons.The pathogenesis of AD pathogenesis is very complex and is associated with a variety of signaling pathways and factors,such as A?,tau protein,neuronal damage,and chronic inflammation.Among the numerous mechanisms,the occurrence and development of Alzheimer's disease is closely related to the microglia-mediated chronic neuroinflammation in the brain,and has received extensive attention and research.Research purposes:Previous laboratory studies have shown that Danggui-Shaoyao-San?DSS?can significantly improve cortical,neuronal,and glial cell damage in the hippocampus induced by D-galactose and AlCl₃.It has a certain role in improving the connection between neuronal cells,neuronal cell structure,improving a variety of organelle functions,and increasing the number of synapses,indicating that Danggui Shaoyao Powder can effectively inhibit the induction of D-galactose combined with AlCl₃ The occurrence and development of rat dementia.However,there is no detailed study on its function in neuroinflammation.The TLR4/NF-?Bsignaling pathway is a classical inflammatory pathway.Considering the important role of neuroinflammation in the occurrence and development of AD,we A series of biological experiments were designed to investigate whether and how DSS can inhibit A?-induced inflammatory responses and TLR4/NF-?B signaling pathways.Research methods:In this study,a model of senile dementia was established by cerebral injection of A?_1-42-42 in C57BL/10JNju mice,and DSS?2 g?crude drug?/mL?was given by gavage for 4 consecutive weeks.The influence of DSS on the memory ability of AD mice induced by A?was determined by measuring Morris water maze locating navigation experiment and space exploration experiment.The changes of brain tissue morphology were observed by observing the pathological changes of brain tissue.The brain tissue CD11b was observed by immunohistochemical method.The expression of microglial cells was detected whether the microglia were activated;the expression of inflammation-associated protein mRNA was detected by RT-PCR;the expression of TLR4/NF-?B signaling pathway-related proteins was detected by Western blot.Subsequently,TLR4 knockout C57BL/10ScNJNju mice were also injected with A?1-42 to establish an AD mouse model.After administration of DSS,the same experimental method was used to verify the relationship between DSS and TLR4/NF-?B signaling pathway.Experimental results:The results showed that DSS can improve the learning and memory ability of AD mice established by A?_1-42.Whether it is a normal mouse or a TLR4 knockout mouse,the escape latency of the water maze is significantly shorter.Histopathological results show that DSS can improve the brain of AD mice.Changes in tissue morphology,enhance cell viability.Immunohistochemistry showed that DSS can reduce the activation of microglia.Further studies have shown that DSS can reduce the expression of TLR4 mRNA and increase the expression of I?B mRNA in the brain of AD mice.It can reduce the expression of TLR4 and p-NF-?B protein in brain tissue,increase the expression of I?B protein and decrease the phosphorylation level in brain of AD mice.The results suggest that DSS can improve the learning and memory ability of AD mice and reduce the inflammatory response in the brain,and its mechanism may be related to the inhibition of the activation of TLR4/NF-?B signaling pathway.However,the results of subsequent TLR4 knockout mice showed that the expression of I?B protein in the brain of mice after A?_1-42-42 injection was increased,the expression of p-NF-?B and p-JNK protein was decreased,and microglia were given after DSS.When activated,the expression of I?B protein decreased,and the expression of p-NF-?B and p-JNK protein increased.The results suggest that loss of TLR4 protein results in A?_1-42failing to activate TLR4/NF-?B signaling pathway,which leads to a decrease in protein phosphorylation.DSS may activate the brain's acute inflammatory response through other pathways to reduce brain damage caused by A?_1-42.