| Theme | Dialysis -- related amyloidosis -- update | |
|---|---|---|
| Title | Molecular mechanisms of amyloid fibril formation | |
| Publish Date | 2001/01 | |
| Author | Hironobu Naiki | The Second Department of Pathology, Fukui Medical University |
| Author | Itaru Yamaguchi | The Second Department of Pathology, Fukui Medical University |
| Author | Kazuhiro Hasegawa | The Second Department of Pathology, Fukui Medical University |
| [ Summary ] | We have proposed that a nucleation-dependent polymerization model could explain the mechanism of amyloid fibril formation in vitro, in various types of amyloidosis including (Abeta2M) amyloidosis. This model consists of two phases, i.e., nucleation and extension phases. Nucleus formation requires a series of association steps of monomers, which are thermodynamically unfavorable. Once the nucleus has been formed, further addition of monomers becomes thermodynamically favorable, resulting in rapid extension of amyloid fibrils. We have developed a first-order kinetic model of amyloid fibril extension in vitro, and confirmed that the extension of amyloid fibrils including Abeta2M amyloid fibrils proceeds via the consecutive association of monomeric precursor proteins onto the ends of existing fibrils. The extension rate of Abeta2M amyloid fibrils was maximum around pH 2.5 and Beta2-microglobulim (Beta2-m) at pH 2.5 has lost much of the secondary and tertiary structures observed at pH7.5. This indicates that partially unfolded amyloidogenic intermediates could readily change their conformation by the catalytic action of the ends of fibrils and polymerize onto the ends of fibrils. Abeta2M amyboid fibrils readily depolymerized into monomeric to oligomeric beta2-m at a neutral pH. Apolipoprotein E, a representative amyloid-associated protein, formed a stable complex with A amyloid fibrils and inhibited their depolymerization at a neutral pH. | |