Repetitive transcranial magnetic stimulation ameliorates the pathology and cognitive dysfunction in a mouse model of Alzheimer's disease through increased drainage efficiency of meningeal lymphatic system

Background Alzheimer’s disease (AD) is a progressive neurodegenerative disease with high prevalence rate among elderly population. Given numerous studies that have shown promising outcomes in delaying or reversing the disease at preclinical stage, however, successful translation into clinical applications has been rare. Repetitive transcranial magnetic stimulation (rTMS) is a non‐invasive, painless technique that has been clinically proven to improve cognitive function in AD patients, but the underlying cellular and molecular mechanisms remain largely uninvestigated. Method 5xFAD mice, an AD mouse model that overexpresses human familiar APP and presenilin 1 mutations under regulated expression of mouse neuronal‐specific Thy1 promotor, were stimulated by rTMS for 2 weeks. The stimulation contained a total of 4000 magnetic stimulation pulses given daily, which consisted of 100 burst trains and 40 pulses of each train at 20 Hz with a 5 sec intertrain interval. At the end of rTMS treatment, mice underwent memory tests including Y‐maze, novel object recognition and novel location recognition. A 10kD Dextran‐AlexaFluo647 tracer was injected into the cisterna magna compartment and mice were perfused 30 minutes later. Brains, meninges and deep cervical lymph nodes were resected for subsequent immunofluorescent analysis. Result 5xFAD mice treated with high frequency rTMS for two weeks showed improved long‐term object and spatial memory, increased neuronal activity as revealed by the elevation of c‐fos ‐positive neurons in the prefrontal cortex and the hippocampus, and reduced pathological features of AD, which included enhanced clearance of β‐amyloid deposit and reduced glial activation. Importantly, rTMS significantly enhanced the drainage of the intra‐cisterna magna injected tracer in 5xFAD mice, as revealed by tracer penetration and clearance in the brain parenchyma, dura mater, and deep cervical lymph nodes. Conclusion Our findings provide the novel mechanistic insight of the regulatory role of rTMS in the drainage efficiency of brain lymphatic system and the clearance of β‐amyloid in the 5xFAD mouse model, suggesting rTMS as a potential tool for the intervention of neurodegenerative and other disorders related to meningeal lymphatic dysfunction.