Mechanism Of Major Depressive Disorder As A Risk Factor In The Development Of Alzheimer's Disease

Objective:Alzheimer's disease(AD)is a neurological degenerative disease.Many studies have shown that there is a close correlation between major depressive disorder(MDD)and AD.MDD increases the risk of AD,and depressive symptoms aggravates the cognitive dysfunction and disease's progression in AD patients.However,the pathological mechanism of MDD as a risk factor for AD remains unclear.The main purpose of this research was to study the effect of chronic unpredictable mild stress(CUMS)on the function of glymphatic system.This study investigated that fluoxetine could play a key role in the function of glymphatic system via regulating the expression of AQP4.The function included the clearance of brain metabolites such as A?42.Methods:1.The mice were randomly divided into two groups with or without CUMS,and each group was randomly divided into saline or fluoxetine groups.2.RT-PCR and immunofluorescence methods were used to detect the effect of fluoxetine on the expression of AQP4 m RNA and protein in the brain of depression model mice.3.The effect of fluoxetine on the function of glymphatic system in depression model mice and TGN-020-treated miceo was detected.4.The effect of fluoxetine on the level of endogenous A?42 in cortex and hippocampus of depressive model mice was detected by immunofluorescence and Western Blot.5.Immunofluorescence was used to detect the effect of fluoxetine on the levels of exogenous A?42 in cortex and hippocampus of depression model mice and TGN-020-treated mice.6.The tests of cognitive and motor activity in depression model mice were detected.Results: 1.Depressive-like behavioral experiments showed that the percentage of sucrose water intake of depression model mice was lower than control group,and the immobility time of the mice in tail suspension and forced swimming experiments was longer than control group.In the open-field experiment,the total traveled distance and the spent time in central area in depression model group were less than control group.And fluoxetine improved depressive-like behavior in depression model mice.2.The m RNA and protein expression of AQP4 in cortex and hippocampus of depression model mice were lower than those in control group,and the decreased expression of AQP4 indepression model mice were increased after fluoxetine treatment.3.The total fluorescence intensity of OA555 and FITC-D3 tracer distributed in depression model group and TGN-020-treated group were lower than those in control group,indicating that the circulatory function of glymphatic system in the brain of depression model mice and TGN-020-treated mice was reduced.Fluoxetine up-regulated the total fluorescence intensity of two tracers distributed in the brains of depression model mice,and improved the circulatory function of glymphatic system of depression model mice.4.The level of endogenous A?42 in cortex and hippocampus of depression model mice was higher than those in control group.The level of endogenous A?42 were decreased in depression model mice treated by fluoxetine.5.The level of exogenous A?42 in cortex and hippocampus of depression model group and TGN-020-treated group was higher than those in control group.The level of exogenous A?42 in the brain of depression model mice was decreased after fluoxetine treatment,but did not change in the TGN-020-treated group.6.Morris water maze and rotarod experiments showed that depression model mice did not cause significant changes in cognitive and motor activity.Conclusion: The expression of AQP4 in astrocytes of depression model mice was reduced,resulting in a decrease in the circulatory function of glymphatic system,which in turn lead to a decrease in the clearance of brain metabolites including A?42.Fluoxetine improved the circulatory function of glymphatic system in the brain of depression model mice by up-regulating AQP4 expression.Major depressive disorder caused a decrease in the expression of AQP4 in the brain,resulting in a decrease in the circulatory function of glymphatic system,which in turn became a risk factor for the onset of AD.