Aβ42 oligomers disrupt calcium homeostasis via Piezo1 and induce neurotoxicity in differentiated SH-SY5Y cells

Abstract Alzheimer's disease (AD) exhibits an intricate and multifactorial pathogenesis. Existing research on amyloid-β (Aβ)-triggered neurotoxicity has predominantly centered on neuronal apoptosis, oxidative stress, and mitochondrial damage. The role of biomechanical signaling, a vital regulatory mechanism in neuronal physiological homeostasis and AD pathological progression, remains largely uncharacterized in the context of Aβ-mediated neurotoxicity. Here, differentiated SH-SY5Y, neuron-like cells, were used to examine the Aβ42 oligomers induced cellular mechanics alteration and the abnormal activation of mechanosensitive ion channels. Aβ42 oligomer adsorption increases cellular Young's modulus, which is associated with sustained intracellular Ca 2+ elevation mediated by Piezo1. Subsequently, the overloaded Ca 2+ induces mitochondrial dysfunction, excessive reactive oxygen species accumulation, YAP/TAZ signaling activation, cytoskeletal remodeling, dynamic changes in cellular stiffness, and finally a cell death through caspase-4-mediated non-canonical pyroptosis. These findings support an Aβ42-Piezo1-Ca 2+ -cytoskeletal remodeling axis that links altered neuronal mechanics to neurotoxicity and identify Piezo1 as a potential target for further investigation in AD.