Kinetic analysis of the polymerization and depolymerization of β 2-microglobulin-related amyloid fibrils in vitro

Abstract

β 2-Microglobulin-related (Aβ 2M) amyloidosis is a serious complication in patients on long-term dialysis, and partial unfolding of β 2-microglobulin (β 2-m) is believed to be prerequisite to its assembly into Aβ 2M amyloid fibrils. Many kinds of amyloid-associated molecules (e.g., apolipoprotein E (apoE), glycosaminoglycans (GAGs), proteoglycans (PGs)) may contribute to the development of Aβ 2M amyloidosis. The formation of Aβ 2M 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 Aβ 2M amyloid fibrils at a neutral pH, inducing partial unfolding of β 2-m and stabilization of the fibrils. Moreover, apoE, GAGs and PGs were found to stabilize Aβ 2M 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 β 2-m. These findings are consistent with the hypothesis that in vivo, specific molecules that affect the conformation and stability of β 2-m and amyloid fibrils will have significant effects on the deposition of Aβ 2M amyloid fibrils.