Lysophospholipids induce the nucleation and extension of β2-microglobulin-related amyloid fibrils at a neutral pH

Background. In beta(2)-microglobulin-related (A beta 2M) amyloidosis, partial unfolding of beta(2)-microglobulin (beta 2-m) is believed to be prerequisite to its assembly into A beta 2M amyloid fibrils in vivo. Low concentrations of sodium dodecyl sulfate induce partial unfolding of beta 2-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 A beta 2M 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 A beta 2M amyloid fibrils at a neutral pH. Results. Some lysophospholipids, especially lysophosphatidic acid (LPA), induced not only the extension of A beta 2M amyloid fibrils but also the formation of A beta 2M amyloid fibrils from the beta 2-m monomer at a neutral pH, by partially unfolding the compact structure of beta 2-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 A beta 2M 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 A beta 2M amyloidosis.