Cell-to-cell transmission of IAPP aggregates in T2DM induces neuronal death by triggering oxidative stress and ferroptosis

Type 2 diabetes mellitus (T2DM) is associated with an elevated risk of neurodegenerative diseases, yet the underlying mechanisms remain elusive. A hallmark feature of T2DM is the amyloid deposition of islet amyloid polypeptide (IAPP) in the pancreas, which may contribute to both pancreatic dysfunction and systemic pathological processes. In this study, we aimed to explore the role of IAPP aggregates as a possible mechanistic link in diabetes-associated neurodegeneration. Using co-culture systems with fluorescently labeled IAPP fibrils, we observed IAPP aggregates transfer between neurons via tunneling nanotubes (TNTs). RNA-seq analysis demonstrated that exposure to IAPP amyloid fibrils triggered substantial alterations in transcriptional profiles, enriching pathways related to oxidative phosphorylation and reactive oxygen species (ROS) production. Mechanistic investigations further showed that IAPP fibrils led to increased ROS levels, mitochondrial dysfunction, and ultimately neuronal death through ferroptosis. Specially, IAPP fibrils disrupted the p62-Keap1 interaction, blocking NRF2 nuclear translocation and altering the expression of ferroptosis-related proteins. Overall, these findings highlight the role of IAPP aggregates in T2DM associated with neurodegeneration, providing new insights into potential therapeutic targets for the relationship between these diseases.