Rapid elongation drives the exceptionally fast aggregation of the most common localized human amyloid medin.

Amyloid deposition is a hallmark of numerous age-related diseases, and understanding the chemical mechanisms that govern amyloid formation is crucial for advancing the rational development of protein aggregation inhibitors. With amyloid formation rates varying widely across proteins, here we report the quantitative aggregation mechanism of medin, the most common localized amyloid in humans, and find it to be much faster compared to well-known pathological amyloids such as amyloid-β (Aβ), tau and α-synuclein. We report the microscopic rate constants and reaction orders of medin fibril formation by monitoring the aggregation of recombinant human medin in vitro via a fluorescence-based assay, global kinetic modeling, secondary structure analysis and electron microscopy. Medin spontaneously forms amyloid fibrils at physiological pH and temperature in quiescent solution at concentrations as low as 25 nM, with the highest fibril elongation rate constant when compared to those of Aβ, tau and α-synuclein. Our results identify the microscopic basis of the widespread observation of medin aggregates upon aging, offering a mechanistic starting point for drug discovery to inhibit medin aggregation.