Glycosaminoglycan and proteoglycan inhibit the depolymerization of beta2-microglobulin amyloid fibrils in vitro.
BACKGROUND
Although several kinds of evidence suggest that glycosaminoglycans (GAGs) and proteoglycans (PGs) may contribute to the development of beta2-microglobulin-related (Abeta2m) amyloidosis, the precise roles of these molecules for the development of Abeta2m amyloidosis are poorly understood.


METHODS
We investigated the effects of GAGs and PGs on the depolymerization of Abeta2m amyloid fibrils at a neutral pH, as well as on the formation of the fibrils at an acidic pH in vitro, using fluorescence spectroscopy with thioflavin T and electron microscopy.


RESULTS
Depolymerization of Abeta2m amyloid fibrils at pH 7.5 at 37 degrees C was inhibited dose-dependently by the presence of some GAGs (heparin, dermatan sulfate, or heparan sulfate) or PGs (biglycan, decorin, or keratan sulfate proteoglycan). Electron microscopy revealed that a significant amount of Abeta2m amyloid fibrils remained in the reaction mixture with some lateral aggregation. Second, when monomeric beta2m was incubated with aggrecan, biglycan, decorin, or heparin at pH 2.5 at 37 degrees C for up to 21 days, the thioflavin T fluorescence increased depending on dose and time. Electron microscopy revealed the formation of rigid and straight fibrils similar to Abeta2m amyloid fibrils in beta2m incubated with biglycan for 21 days.


CONCLUSIONS
These results suggest that some GAGs and PGs could enhance the deposition of Abeta2m amyloid fibrils in vivo, possibly by binding directly to the surface of the fibrils and stabilizing the conformation of beta2m in the fibrils, as well as by acting as a scaffold for the polymerization of beta2m into the fibrils.
Yamaguchi
Itaru
I
Department of Pathology, Fukui Medical University, Fukui, Japan.
Suda
Hironori
H
Tsuzuike
Naoki
N
Seto
Kouichi
K
Seki
Masaharu
M
Yamaguchi
Yukiya
Y
Hasegawa
Kazuhiro
K
Takahashi
Naoki
N
Yamamoto
Suguru
S
Gejyo
Fumitake
F
Naiki
Hironobu
H
D000682:Amyloid / Q000378:metabolism* / Q000648:ultrastructure; D004305:Dose-Response Relationship, Drug; D006025:Glycosaminoglycans / Q000008:administration & dosage / Q000502:physiology*; D006493:Heparin / Q000494:pharmacology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008854:Microscopy, Electron; D011108:Polymers / Q000378:metabolism*; D011509:Proteoglycans / Q000008:administration & dosage / Q000502:physiology*; D011994:Recombinant Proteins / Q000378:metabolism; D013050:Spectrometry, Fluorescence; D001613:beta 2-Microglobulin / Q000378:metabolism*
D000682:Amyloid; D006025:Glycosaminoglycans; D011108:Polymers; D011509:Proteoglycans; D011994:Recombinant Proteins; D001613:beta 2-Microglobulin; D006493:Heparin