Glycosaminoglycans enhance the trifluoroethanol-induced extension of beta 2-microglobulin-related amyloid fibrils at a neutral pH.
beta(2)-Microglobulin-related (A beta 2M) amyloidosis is a frequent and serious complication in patients on long-term dialysis, and beta(2)-microglobulin is a major structural component of A beta 2M amyloid fibrils. Several biologic molecules inhibiting the depolymerization of A beta 2M amyloid fibrils at a neutral pH were found recently. The effect of trifluoroethanol and glycosaminoglycans (GAG) on the extension of the fibrils at a neutral pH was investigated with the use of fluorescence spectroscopy with thioflavin T, circular dichroism spectroscopy, and electron microscopy. Trifluoroethanol at concentrations of up to 20% (vol/vol) caused fibril extension of heparin-stabilized seeds, inducing a subtle change in the tertiary structure of beta(2)-microglobulin and stabilizing the fibrils at a neutral pH. This extension reaction followed a first-order kinetic model. In addition, some GAG, especially heparin, dose-dependently enhanced the fibril extension. These results suggest that some GAG, especially heparin, may bind to the fibrils and enhance their deposition in vivo. Thus, the experimental system described here should be useful to search for the factors that accelerate A beta 2M amyloid deposition in vivo. In addition, the interference of the binding of GAG to A beta 2M amyloid fibrils may be an attractive therapeutic modality.
Yamamoto
Suguru
S
Department of Pathology, Fukui Medical University, Fukui, Japan.
Yamaguchi
Itaru
I
Hasegawa
Kazuhiro
K
Tsutsumi
Shinobu
S
Goto
Yuji
Y
Gejyo
Fumitake
F
Naiki
Hironobu
H
D000682:Amyloid / Q000187:drug effects / Q000378:metabolism*; D006025:Glycosaminoglycans / Q000494:pharmacology*; D006863:Hydrogen-Ion Concentration; D014270:Trifluoroethanol / Q000494:pharmacology*; D001613:beta 2-Microglobulin / Q000187:drug effects / Q000378:metabolism*
D000682:Amyloid; D006025:Glycosaminoglycans; D001613:beta 2-Microglobulin; D014270:Trifluoroethanol