Abstract
This study aimed to investigate the impact of repetitive transcranial magnetic stimulation (rTMS) on cognitive recovery in Alzheimer's disease (AD) by exploring the role of GABAergic neuron activation and modulation of the Cx3cl1-Cx3cr1 signalling axis. The 5xFAD mouse model was utilised for scRNA-seq analysis to examine changes in gene expression post-rTMS. Microglial phagocytic activity, amyloid plaque burden, cell-cell communication, microglial morphology and neuroinflammation markers were assessed. Following rTMS, upregulation of Cx3cl1 in GABAergic neurons was observed, leading to enhanced microglial phagocytosis, reduced amyloid plaque burden, improved cell-cell communication, altered microglial morphology and decreased neuroinflammation markers. This study demonstrates that rTMS promotes Aβ clearance and cognitive recovery in AD by activating GABAergic neurons and enhancing Cx3cl1-Cx3cr1 signalling, providing a novel molecular target for non-invasive AD therapy. These findings support the transition from invasive to non-invasive AD treatments, improving patient adherence and therapeutic outcomes. Furthermore, the elucidation of cellular and molecular mechanisms facilitates drug development targeting the Cx3cl1-Cx3cr1 axis, offering new opportunities for AD intervention.