Molecular interactions in the formation and deposition of β2-microglobulin-related amyloid fibrils

Abstract

In β2-microglobulin-related (Aβ2M) amyloidosis, a serious complication in patients on long-term dialysis, partial unfolding of β2-microglobulin (β2-m) is believed to be prerequisite to its assembly into Aβ2M amyloid fibrils. Many kinds of amyloid-associated molecules, (e.g., apolipoprotein E (apoE), glycosaminoglycans (GAGs), proteoglycans (PGs)) may contribute to the development of Aβ2M amyloidosis. In 1990s, the formation of Aβ2M amyloid fibrils in vitro was first observed at low pH (2.0–3.0). Very recently, low concentrations of 2,2,2-trifluoroethanol (TFE) and the sub-micellar concentration of sodium dodecyl sulfate, a model for anionic phospholipids, have been reported to cause the extension of Aβ2M amyloid fibrils at a neutral pH, inducing partial unfolding of β2-m and stabilization of the fibrils. Moreover, apoE, GAGs, and PGs were found to stabilize Aβ2M amyloid fibrils at a neutral pH, forming a stable complex with the fibrils. Some GAGs, especially heparin, enhanced the fibril extension in the presence of TFE at a neutral pH. Some PGs, especially biglycan also induced the polymerization of acid-denatured β2-m. These findings are consistent with the hypothesis that in vivo, specific molecules that affect the conformation and stability of β2-m and amyloid fibrils will have significant effects on the deposition of Aβ2M amyloid fibrils.