Cross-Interactions of Amyloid Proteins: Implications for Aggregation Dynamics and Disease Pathology

Amyloid aggregation is a pervasive form of protein misfolding implicated in the pathology of several prominent human diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and type 2 diabetes (T2D). These diseases are marked by the accumulation of amyloid fibrils and toxic oligomers, which are highly dynamic and heterogeneous, posing challenges for understanding their roles in disease progression. Despite significant advances in the diagnosis and management of these conditions, no definitive cure is available. We investigate amyloid aggregation and cross-seeding, with a focus on amyloid-beta (Aβ), tau, alpha-synuclein (αS), and human islet amyloid polypeptide (IAPP) through discrete molecular dynamics (DMD) simulations. Beta-casein-coated iron oxide nanoparticles were evaluated as inhibitors of amyloid aggregation. These nanoparticles displayed Janus properties and promising therapeutic potential against amyloid diseases. Additionally, we identified specific Aβ-tau binding hotspots in AD, with tau repeats showing distinct binding preferences at the lateral and elongation surfaces of Aβ fibrils, highlighting their roles in facilitating tau aggregation. The cross-seeding behavior of Aβ and IAPP, relevant to the crosstalk between AD and T2D, revealed that while Aβ and IAPP cannot co-assemble due to sequence mismatches, preformed IAPP fibrils accelerate Aβ nucleation. Furthermore, we investigated the impact of SARS-CoV-2 spike protein fragments on Aβ aggregation, identifying a fragment with high amyloidogenicity and strong binding to Aβ. This interaction enhanced Aβ aggregation, suggesting a potential link between COVID-19 and neurodegenerative outcomes. These findings deepen our understanding of amyloid aggregation and cross-seeding, offering insights into the molecular mechanisms of these diseases and potential therapeutic interventions.