Glycosaminoglycans Enhance the Trifluoroethanol-Induced... : Journal of the American Society of Nephrology (original) (raw)

Basic Dialysis

Glycosaminoglycans Enhance the Trifluoroethanol-Induced Extension of β2-Microglobulin–Related Amyloid Fibrils at a Neutral pH

Yamamoto, Suguru*,†; Yamaguchi, Itaru*; Hasegawa, Kazuhiro*; Tsutsumi, Shinobu*; Goto, Yuji‡,§; Gejyo, Fumitake†; Naiki, Hironobu*,§

*Department of Pathology, Fukui Medical University, Fukui, Japan; †Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Science, Niigata, Japan; ‡Institute for Protein Research, Osaka University, Osaka, Japan; and §CREST of Japan Science and Technology Corporation, Saitama, Japan

Correspondence to Dr. Hironobu Naiki, Department of Pathology, Fukui Medical University, Fukui 910-1193, Japan. Phone: +81-776-61-8320; Fax: +81-776-61-8123;

Accepted October 05, 2003

Received July 19, 2003

Abstract

ABSTRACT. β2-Microglobulin–related (Aβ2M) amyloidosis is a frequent and serious complication in patients on long-term dialysis, and β2-microglobulin is a major structural component of Aβ2M amyloid fibrils. Several biologic molecules inhibiting the depolymerization of Aβ2M 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 β2-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 Aβ2M amyloid deposition in vivo. In addition, the interference of the binding of GAG to Aβ2M amyloid fibrils may be an attractive therapeutic modality. E-mail: [email protected]