| [ Summary ] |
beta2-Microgllobulin-related (Abeta2-m) amyloidosis is a common and serious complication in patients on long-term dialysis. The mechanism of the deposition of these Abeta2-m amyloid fibrils is still unknown. We investigated the mechanisms of amyloid fibril formation, using fluorescence spectroscopy with thioflavin T, circular dichroism spectroscopy, electron microscopy and other modalities. We, and other groups, have proposed that a nucleation-dependent polymerization model could explain the general mechanisms of amyloid fibril formation in vitro, in various types of human amyloidosis. In the 1990s, the formation of Abeta2-m amyloid fibrils in vitro was first observed at low pH (2.0 - 3.0). After that, the sub-micellar concentration of sodium dodecyl sulfate, a model for anionic phospholipids, was reported to cause the extension of Abeta2-m amyloid fibrils at a neutral pH, inducing partial unfolding of beta2-microgllobulin (beta2-m) and stabilization of the fibrils. Moreover, apoE, GAGs, and PGs were found to stabilize Abeta2-m amyloid fibrils at a neutral pH, forming a stable complex with the fibrils. Very recently, we reported that some lysophospholipids and non-esterified fatty acids induced the extension of Abeta2-m amyloid fibrds at a neutral pH, by partially unfolding the compact structure of beta2-m to an amyloidogenic conformer, as well as stabilizing the extended fibrils. These findings are consistent with the hypothesis that in vitro, specific molecules that affect the conformation and stability of beta2-m and amyloid fibrils will have significant effects on the deposition of Abeta2-m amyloid fibrils. |