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Nephrol Dial Transplant. 2008 Oct;23(10):3247-55. doi: 10.1093/ndt/gfn231. Epub 2008 May 8.

Lysophospholipids induce the nucleation and extension of beta2-microglobulin-related amyloid fibrils at a neutral pH.

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1
Department of Pathological Sciences, Division of Molecular Pathology, Faculty of Medical Sciences, University of Fukui, Fukui 910-1193, Japan.

Abstract

BACKGROUND:

In beta(2)-microglobulin-related (Abeta2M) amyloidosis, partial unfolding of beta(2)-microglobulin (beta2-m) is believed to be prerequisite to its assembly into Abeta2M amyloid fibrils in vivo. Low concentrations of sodium dodecyl sulfate induce partial unfolding of beta2-m to an amyloidogenic conformer and subsequent amyloid fibril formation in vitro, but the biological molecules that induce them under near-physiological conditions have not been determined.

METHODS:

We investigated the effect of some lysophospholipids on the nucleation, extension and stabilization of Abeta2M amyloid fibrils at a neutral pH, using fluorescence spectroscopy with thioflavin T, circular dichroism spectroscopy and electron microscopy. We also measured plasma concentrations of lysophospholipids in 103 haemodialysis patients and 14 healthy subjects and examined the effect of uraemic and normal plasmas on the stabilization of Abeta2M amyloid fibrils at a neutral pH.

RESULTS:

Some lysophospholipids, especially lysophosphatidic acid (LPA), induced not only the extension of Abeta2M amyloid fibrils but also the formation of Abeta2M amyloid fibrils from the beta2-m monomer at a neutral pH, by partially unfolding the compact structure of beta2-m to an amyloidogenic conformer as well as stabilizing the extended fibrils. Haemodialysis patients had significantly higher plasma concentrations of LPA than healthy subjects. Furthermore, uraemic plasmas with the highest ranking LPA concentrations stabilized Abeta2M amyloid fibrils significantly more potently than normal plasmas. On the other hand, simple addition of LPA to normal plasma did not enhance the fibril stabilizing activity.

CONCLUSIONS:

These results suggest a possible role of lysophospholipids in the development of Abeta2M amyloidosis.

PMID:
18467373
DOI:
10.1093/ndt/gfn231
[Indexed for MEDLINE]
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