The crowded environment of a reverse micelle induces the formation of β-strand seed structures for nucleating amyloid fibril formation.

A hallmark of Alzheimer's disease is the accumulation of insoluble fibrils in the brain composed of amyloid beta (Aβ) proteins with parallel in-register cross-β-sheet structure. It has been suggested that the aggregation of monomeric Aβ proteins into fibrils is promoted by "seeds" that form within compartments of the brain that have limited solvent due to macromolecular crowding. To characterize these seeds, a crowded macromolecular environment was mimicked by encapsulating Aβ40 monomers into reverse micelles. Fourier-transform infrared spectroscopy revealed that monomeric Aβ proteins form extended β-strands in reverse micelles, while an analogue with a scrambled sequence does not. This is a remarkable finding, because the formation of extended β-strands by monomeric Aβ proteins suggests a plausible mechanism whereby the formation of amyloid fibrils may be nucleated in the human brain.