Neuroprotective Effect Of Electrical Stimulation Of Nucleus Basalis Of Meynert In Transgenic Mice With Alzheimer's Disease

Alzheimer's disease(AD)is the most common type of dementia and now mainly treated by medicines,but the treatment effect is very limited.Deep brain stimulation(DBS)is a neurosurgical procedure involving the implantation of a medical device called a neurostimulator,which delivers electrical signals to the areas of the brain that control movement.Some case reports over the use of DBS for AD patients have indicated good efficacy.This study discussed the optimal parameters of DBS for treating the animal model of AD and proposed the mechanism of the treating effect.APP/PS1 transgenic mice were selected and received DBS of nucleus basalis of Meynert(NBM).Different stimulation intensities(10 Hz,50 Hz,100 Hz,130 Hz)and durations(7 d,14 d,21 d,28 d)were used for mice of different age(4 months,6 months,9 months,12 months).Then water maze test consisting of spatial navigation and exploration was performed to determine the optimal parameters of DBS for treating AD.Nissl and NeuN staining was performed for the neurons;apoptotic cells were detected by TUNEL assay and using Hoechst dye;apoptosis-related proteins were detected by Western Blot.The activities of superoxide dismutase(SOD),glutathione peroxidase(GSH-Px),acetylcholinesterase(AChE)and choline acetyltransferase(Ch AT)were detected along with the content of malondialdehyde(MDA).The phosphorylated proteins of several signaling pathways were detected and their role was determined with the use of relevant inhibitors.In water maze test,the escape latency of the mice aged 4 months which received DBS at 100 Hz frequency for 21 d was obviously reduced as compared with other mice;moreover,the number of times of passing through the quadrant/platform was increased significantly.Under the above combination of parameters,the soluble A?40 and A?42 in the hippocampus were down-regulated significantly.So this combination was used for the subsequent experiment.According to the results,DBS increased the number of surviving neurons in the hippocampus and reduced cell apoptosis in APP/PS1 transgenic mice;the apoptosis-related proteins caspase-3,caspase-8 and Bid were down-regulated,while the expressions of caspase-9,Bax and Bcl-2 were not affected.Moreover,DBS caused a significant increase in SOD,GSH-Px and ChAT activity and a decrease in MDA content and AChE activity.The phosphorylated Akt was up-regulated and the phosphorylated ERK was down-regulated.Both ERK inhibitor U0126 and PI3 K inhibitor LY294002 reduced the escape latency,increased the number of times of passing through the quadrant/platform and down-regulated A?.We found that early DBS(starting from 4 months of age)for 21 d at high frequency(100 Hz)activated PI3K/Akt signaling pathway and inhibited ERK pathway.DBS under these parameters can best improve the cognitive function,increase neuronal survival,relieve cell apoptosis and oxidative stress and regulate ACh pathway in mice with AD.To conclude,NBM-DBS can serve as a candidate therapy for AD.