Amyloid aggregates sharing cross-β sheet structure

Amyloid aggregates are insoluble protein fibrils characterized by a signature cross-β sheet quaternary structure, where individual β-strands are oriented perpendicular to the long axis of the fibril (Sipe et al., 2016). This highly stable and protease-resistant motif arises from the misfolding and polymerization of various precursor proteins, including amyloid-beta, tau, alpha-synuclein, and transthyretin (Chiti & Dobson, 2017). The accumulation of these aggregates is a central pathological hallmark of over 50 human diseases, most notably neurodegenerative conditions like Alzheimer's and Parkinson's, where they exert proteotoxicity and disrupt cellular homeostasis. Therapeutic strategies focus on preventing the formation of these structures, neutralizing toxic oligomeric intermediates, or enhancing their clearance from tissues using monoclonal antibodies (FDA, 2023). Recent clinical advancements have validated these structural aggregates as critical targets, with several approved therapies specifically designed to recognize and bind the amyloid fold to mitigate disease progression. Understanding the biophysical properties of the cross-β sheet remains essential for developing next-generation interventions that can effectively target the universal features of protein misfolding.

Other names

Amyloid fibrilsCross-beta sheet aggregatesMisfolded protein aggregatesPathological protein assembliesAmyloid plaquesAmyloidogenic folds

Therapeutic agents targeting these structures typically function by inhibiting the nucleation and elongation of fibrils, stabilizing the native monomeric state of precursor proteins to prevent misfolding, or utilizing monoclonal antibodies to facilitate the immunological clearance of existing aggregates via microglial phagocytosis. Some pan-amyloid agents, such as those employing the General Amyloid Interaction Motif (GAIM), directly bind and remodel the universal cross-β sheet structure to promote disaggregation.