Study On The Therapeutic Effects And Mechanisms Of Repetitive Transcranial Magnetic Stimulation In Mice Models Of Alzheimer's Disease And Alzheimer's Disease With Comorbid Depression

Objective:Alzheimer's disease(AD)is a neurodegenerative disease with high morbidity and disability.Its clinical manifestations include cognitive dysfunction and non-cognitive symptoms,among which depression is the most common non-cognitive symptom.Repetitive transcranial magnetic stimulation(r TMS)is widely used in the treatment of a variety of neurological diseases,such as AD,depression,schizophrenia and stroke,but its mechanism remains unclear.The purpose of this study was to investigate the therapeutic effects and mechanisms of repetitive transcranial magnetic stimulation(r TMS)in mice models of alzheimer's disease(AD)and AD with comorbid depression.Methods:1.3x Tg-AD model mice were treated with 25 Hz r TMS for 21 days.The Morris water maze test was used to evaluate the effect of r TMS on the cognitive function.The levels of A?and pro-inflammatory cytokines were assessed by ELISA;Oxidative stress was assessed by biochemical assay;Neuroinflammation and neuronal survival were assessed by immunofluorescence;Apoptosis was assessed by TUNEL staining;Brain glucose metabolism was assessed by ¹⁸F-FDG PET;Synaptic plasticity and protein expression of PI3K/Akt/GLT-1 pathway were assessed by western blot.In the second part of the experiment,to explore the impact of inhibiting PI3K/Akt activity on the therapeutic effects of r TMS,3x Tg-AD model mice were given LY294002 intervention and r TMS treatment for 21 days,and the experimental methods were the same as before.2.3x Tg-AD mice were exposed to chronic unpredictable mild stress(CUMS)for two months to establish a model of depression associated with AD and were treated with r TMS and sertraline respectively.The sucrose preference test,forced swimming test and open-field test were used to evaluate depression-like behavior,and the Morris water maze test was used to evaluate cognitive function.A?levels were assessed by ELISA;Neuroinflammation and neuronal survival were assessed by immunofluorescence;Apoptosis was assessed by TUNEL staining;The m RNA and protein expressions of NMDARs and related pathways were assessed by q RT-PCR and western blot.Results:1.We found that 25 Hz r TMS can improve cognitive function of 3x Tg-AD model mice,reduce hippocampus A?1-42 level,alleviate oxidative stress and neuroinflammatory response,improve glucose metabolism,enhance synaptic plasticity and reduce neuronal loss and cell apoptosis,accompanied by activation of PI3K/Akt/GLT-1 pathway.After administration of PI3K/Akt inhibitor LY294002,25 Hz r TMS could not improve the cognitive function,decrease the level of A?1-42 and reduce neuronal damage of 3x Tg-AD model mice,nor could it upregulate the expression of GLT-1.Therefore,25 Hz r TMS can regulate the pathological process of 3x Tg-AD model mice from various aspects,and its therapeutic and protective effects depend on the activity of PI3K/Akt/GLT-1 pathway.2.Behavioral tests revealed that CUMS not only induced depression-like behaviors,but further damaged spatial learning and memory in 3x Tg-AD mice.Meanwhile,we found that r TMS simultaneously ameliorated depressive and cognitive symptoms in CUMS-exposed 3x Tg-AD mice.r TMS also reduced A?levels,relieved neuroinflammation,up-regulated NR2B expression,prevented neuronal loss and apoptosis.The above therapeutic effects might be related to the regulation of Homer1a/CDK5/GR signaling and GLT-1 expression by r TMS.Conclusion:High frequency r TMS is an effective method for the treatment of AD which can regulate a variety of pathological processes in the brain.Our study provides the first evidence for the therapeutic effects of r TMS on depression in AD.This study provides new theoretical basis for revealing the mechanism of r TMS in AD and provides a new direction for the clinical treatment of AD.