• Substrate stiffness modulates Aβ42-induced neurotoxicity: stiff substrates exacerbate cell death, synaptic loss, and impaired Ca2+ oscillations, while soft substrates confer protection.
• Aβ42 disrupts spontaneous Ca2+ oscillations and synaptic transmission more severely on stiff ECM, mimicking the stiffening observed in AD brains.
• Findings suggest that ECM stiffness is a critical biophysical factor in AD pathology, offering a potential target for therapeutic intervention.
• The study provides a novel in vitro model to investigate the interplay between mechanical microenvironment and neurodegenerative processes.