High frequency repetitive transcranial magnetic stimulation alleviates cognitive deficits in 3xTg-AD mice by modulating the PI3K/Akt/GLT-1 axis

Glutamate mediated excitotoxicity, such as oxidative stress, neuroinflammation, synaptic loss and neuronal death, is ubiquitous in Alzheimer's disease (AD). Our previous study found that 15 Hz repetitive transcranial magnetic stimulation (rTMS) could reduce cortical excitability. The purpose of this study was to explore the therapeutic effect of higher frequency rTMS on 3xTg-AD model mice and further explore the mechanisms of rTMS.First, WT and 3xTg-AD model mice received 25 Hz rTMS treatment for 21 days. The Morris water maze test was used to evaluate the cognitive function. The levels of Aβ and neuroinflammation were assessed by ELISA and immunofluorescence. Oxidative stress was quantified by biochemical assay kits. Brain glucose metabolism was assessed by 18F-FDG PET. Apoptosis was assessed by western blot and TUNEL staining. Synaptic plasticity and PI3K/Akt/GLT-1 pathway related protein expression were assessed by western blot. Next, to explore the activity of PI3K/Akt in the therapeutic effect of rTMS, 3xTg-AD model mice were given LY294002 intervention and rTMS treatment for 21 days, the experimental method was the same as before.We found that 25 Hz rTMS could improve cognitive function of 3xTg-AD model mice, reduce hippocampal Aβ1-42 levels, ameliorate oxidative stress and improve glucose metabolism. rTMS alleviated neuroinflammatory response, enhanced synaptic plasticity and reduced neuronal loss and cell apoptosis, accompanied by activation of PI3K/Akt/GLT-1 pathway. After administration of PI3K/Akt inhibitor LY294002, 25 Hz rTMS could not improve the cognitive function and reduce neuron damage of 3xTg-AD model mice, nor could it upregulate the expression of GLT-1, indicating that its therapeutic and protective effects required the involvement of PI3K/Akt/GLT-1 pathway.rTMS exerts protective role for AD through regulating multiple pathological processes. Meanwhile, this study revealed the key role of PI3K/Akt/GLT-1 pathway in the treatment of AD by rTMS, which might be a new target.