40 Hz vibrotactile stimulation ameliorates amyloid pathology and cognitive deficits in 5xFAD mice and is associated with alterations in Piezo1, ERK, and GSK-3β/p65 signaling.

40 Hz vibrotactile stimulation (VTS) is an emerging non-invasive therapy for Alzheimer's disease (AD), yet its specific mechanisms regarding amyloid-beta (Aβ) metabolism remain unclear. Six-month-old 5xFAD mice received daily 40 Hz VTS for four weeks. We assessed cognitive function, Aβ pathology, and underlying molecular pathways. VTS improved spatial learning and recognition memory, whereas no significant improvement was observed in short-term spatial working memory. VTS reduced hippocampal Aβ plaque burden and cortical soluble Aβ40 and Aβ42 levels, accompanied by decreased expression of APP, BACE1, and PS1 and increased expression of ADAM10 and IDE. It further attenuated neuroinflammation, oxidative stress and produced changes in cholinergic and synaptic plasticity-associated proteins. VTS increased hippocampal Piezo1 expression and ERK phosphorylation, increased inhibitory phosphorylation of GSK-3β at Ser9, decreased p65 phosphorylation, and reduced tau phosphorylation. 40 Hz VTS ameliorates several cognitive and neuropathological features of AD in 5xFAD mice. These improvements are associated with the modulation of Piezo1, ERK, and GSK-3β/p65 signaling pathways, highlighting its potential as a promising non-invasive AD therapeutic strategy.