Alzheimer’s disease (AD) and type 2 diabetes (T2D) are two of the most widespread age-related disorders, affecting millions of people worldwide. Growing clinical evidence reveals a strong bidirectional association between them: individuals with T2D face a significantly higher risk of developing AD, and patients with AD are more likely to exhibit metabolic dysfunctions. Pathologically, the two diseases are characterized by the deposition of distinct amyloidogenic peptides—amyloid-β (Aβ), which forms senile plaques in the brain in AD, and human islet amyloid polypeptide (hIAPP or amylin), which aggregates within pancreatic islets in T2D. Increasing attention has therefore turned to the possibility of molecular cross-talk between these peptides. In this work, we investigate how Aβ and hIAPP influence each other’s aggregation pathways and conformational transitions. At sub-micromolar concentrations, we probed their early-stage co-assembly during the lag phase of fibril formation. A combination of spectroscopic and imaging methods, including static light scattering, FTIR, thioflavin-T fluorescence, intrinsic photoluminescence, transmission electron microscopy, and impedance spectroscopy, revealed distinct asymmetry in their interactions. Specifically, hIAPP accelerates Aβ aggregation by reducing the lag phase and facilitating β-sheet conversion, while Aβ slows hIAPP aggregation, likely by binding and masking its aggregation-prone segments. To complement these experimental insights, we performed molecular simulations that identified the interaction interfaces mediating this cross-talk. Together, these findings uncover a directional and asymmetric cross-seeding mechanism between Aβ and hIAPP, providing a molecular framework for understanding the pathogenic link between T2D and AD.
Sarangi et al. (Sun,) studied this question.