Endogenous Aβ and Exogenous Wheat Gluten Nanostructures: Understanding Peptide Self-Assembly in Disease.

The self-assembly of endogenous and exogenous peptides into proteolysis-resistant oligomers can trigger toxic cellular events and diseases. In Alzheimer's disease (AD), the structural polymorphisms of endogenous amyloid-β (Aβ) 1-40 and 1-42 aggregates are essential for their neurotoxic effects. Recent findings on structural differences between brain-derived and fibrils underscore the need to improve the molecular and supramolecular models of diseases, for example, by stabilizing monomer conformations that lead to disease-relevant structures. In gluten-related disorders (GRDs), particularly celiac disease (CeD), research focuses on exogenous proteolytically resistant gliadin peptides (PRGPs) such as the 33-mer, p31-43, and pepsin-trypsin-derived gliadin peptides. Notably, these PRGPs form nanostructures, which may explain their behavior as nonreplicating pathogens. Thus, understanding their self-assembly has recently gained attention. This review invites both newcomers and experts in the field to tackle the challenges of characterizing peptide self-assembly process as first step to develop successful therapeutic interventions. For AD researchers, it highlights protocols for obtaining monomers and their supramolecular characterization to uncover mechanisms of brain-derived fibril formation, while also showcasing opportunities to explore PRGP nanostructures. For GRD researchers, it offers protocols to obtain PRGP nanostructures and their thorough characterization prior to cellular studies, inspired by approaches in AD research. This review contributes to interdisciplinary efforts toward therapeutic strategies grounded in molecular and supramolecular data by outlining structural insights, characterization protocols, and existing knowledge gaps. Its final aim is to connect established and emerging research domains related to Aβ and gliadin peptides that may have potential applications in peptide self-assembly and the gut-brain axis research, respectively.