Study On Micheliolide Improving AD Model Mice Cognitive Impairment And Its Mechanism

Alzheimer's disease(AD)is the most common degenerative disease of the central nervous system,characterized by progressive cognitive impairment,extracellular amyloid deposition,intracellular neurofibrillary tangles,neuronal death and chronic inflammation in the brain.This study explored the improving effect of micheliolide(MCL)on AD cognitive impairment and its possible mechanism.The5×FAD model mice were fed with MCL for 3 months.The improving effect of MCL on learning and memory impairment of AD mice and the inhibition of inflammation in mice were analyzed at 5 months of age.New object recognition experiments showed that MCL could increase the percentage of time and frequency of mice exploring new things.The water maze experiment showed that MCL could shorten the escape latency of mice during positioning voyage,and increase the time of mice staying in the target quadrant and the frequency of crossing the platform during space exploration.Thio-S staining showed that MCL could significantly reduce the number of A?plaques in hippocampus DG,CA1 area and cortex of mice.Immunohistochemistry analysis showed that MCL could significantly reduce the number of Iba1~+microglia cells in the hippocampus DG,CA1 area and cortex of mice,and inhibit the abnormal activation and aggregation of microglias.MCL could also reduce the number of GFAP~+astrocytes in mouse brain and inhibit the activation of astrocytes.The detection of inflammatory factors showed that MCL could inhibit the secretion of proinflammatory factors such as MIP-1??IL-1??IL-4?G-CSF?GM-CSF?MIP-?in mice brain and IL-1??IL-17A?MCP-1?IL-1??IL-12p40?IL-12p70?TNF-??G-CSF?MIP-1?in mice peripheral,and increase the secretion of anti-inflammatory factors such as IL-10,CXCL1,CCL5 and CCL11.Complete blood count analysis showed that MCL could inhibit the infiltration of inflammatory cells such as neutrophils,lymphocytes and monocytes in peripheral blood of mice.In vitro cell experiments showed that MCL could inhibit microglias activation induced by LPS.q RT-PCR analysis showed that MCL could inhibit the expression of IL-1??TNF-??COX-2 and i NOS in LPS-activated microglias.Western-blot analysis showed that MCL could inhibit the phosphorylation of p-I?B?p-p65 and p-AKT in LPS-activated microglias.In conclusion,MCL could reduce the intensity of systemic inflammatory response in AD mice by inhibiting the infiltration of peripheral inflammatory cells,reducing the secretion of pro-inflammatory factors in peripheral blood.MCL also inhibited the secretion of pro-inflammatory factors in the brain,inhibited the abnormal activation and proliferation of glial cells,reduced the formation and accumulation of A?plaques in the hippocampus and cortex of the AD mice brain,alleviated the inflammatory damage to neurons,thus MCL could improve the learning and memory impairment in 5×FAD model mice.