αB-crystallin, a small heat-shock protein, prevents the amyloid fibril growth of an amyloid β-peptide and β2-microglobulin

alpha B-crystallin, a small heat-shock protein, exhibits molecular chaperone activity. We have studied the effect of alpha B-crystallin on the fibril growth of the A beta (amyloid beta)-peptides A beta-(1-40) and A beta(1-42). alpha B-crystallin, but not BSA or hen egg-white lysozyme, prevented the fibril growth of A beta-(1-40), as revealed by thioflavin T binding, total internal reflection fluorescence microscopy and CD spectroscopy. Comparison of the activity of some mutants and chimaeric alpha-crystallins in preventing A beta-(1-40) fibril growth with their previously reported chaperone ability in preventing dithiothreitol-induced aggregation of insulin suggests that there might be both common and distinct sites of interaction on alpha-crystallin involved in the prevention of amorphous aggregation of insulin and fibril growth of A beta-(1-40). alpha B-crystallin also prevents the spontaneous fibril formation (without externally added seeds) of A beta-(1-42), as well as the fibril growth of A beta(1-40) when seeded with the A beta-(1-42) fibril seed. Sedimentation velocity measurements show that alpha B-crystallin does not form a stable complex with A beta-(1-40). The mechanism by which it prevents the fibril growth differs from the known mechanism by which it prevents the amorphous aggregation of proteins. aB-crystallin binds to the amyloid fibrils of A beta-(1-40), indicating that the preferential interaction of the chaperone with the fibril nucleus, which inhibits nucleation-dependent polymerization of amyloid fibrils, is the mechanism that is predominantly involved. We found that alpha B-crystallin prevents the fibril growth of beta(2)-microglobulin under acidic conditions. It also retards the depolymerization of beta 2-microglobulin fibrils, indicating that it can interact with the fibrils. Our study sheds light on the role of small heat-shock proteins in protein conformational diseases, particularly in Alzheimer's disease.