Molecular interactions in the formation and deposition of β₂-microglobulin-related amyloid fibrils

Abstract

In β₂-microglobulin-related (Aβ₂M) amyloidosis, a serious complication in patients on long-term dialysis, partial unfolding of β₂-microglobulin (β₂-m) is believed to be prerequisite to its assembly into Aβ₂M amyloid fibrils. Many kinds of amyloid-associated molecules, (e.g., apolipoprotein E (apoE), glycosaminoglycans (GAGs), proteoglycans (PGs)) may contribute to the development of Aβ₂M amyloidosis. In 1990s, the formation of Aβ₂M amyloid fibrils in vitro was first observed at low pH (2.0–3.0). Very recently, low concentrations of 2,2,2-trifluoroethanol (TFE) and the sub-micellar concentration of sodium dodecyl sulfate, a model for anionic phospholipids, have been reported to cause the extension of Aβ₂M amyloid fibrils at a neutral pH, inducing partial unfolding of β₂-m and stabilization of the fibrils. Moreover, apoE, GAGs, and PGs were found to stabilize Aβ₂M amyloid fibrils at a neutral pH, forming a stable complex with the fibrils. Some GAGs, especially heparin, enhanced the fibril extension in the presence of TFE at a neutral pH. Some PGs, especially biglycan also induced the polymerization of acid-denatured β₂-m. These findings are consistent with the hypothesis that in vivo, specific molecules that affect the conformation and stability of β₂-m and amyloid fibrils will have significant effects on the deposition of Aβ₂M amyloid fibrils.

• β2-microglobulin
• amyloidosis
• hemodialysis
• glycosaminoglycans
• proteoglycans 2,2,2-trifluoroethanol
• sodium dodecyl sulfate
• partial unfolding
• amyloid fibrils

AA, amyloid protein A; AApoAII, apolipoprotein A-II-related murine senile; Aβ, amyloid β-peptide; Aβ₂M, β₂-microglobulin-related; AIAPP, islet amyloid polypeptide (amylin)-related; AL, immunoglobulin light chain-related; apoE, apolipoprotein E; apoSAA, serum amyloid A; β₂-m, β₂-microglobulin; CD, circular dichroism; CMC, critical micelle concentration; CS, chondroitin sulfate; CSA, chondroitin sulfate A; CSC, chondroitin sulfate C; DS, dermatan sulfate; DTAC, dodecyl trimethyl ammonium chloride; GAGs, glycosaminoglycans; GM1, GM1 ganglioside; HA, hyaluronic acid; HS, heparan sulfate; HSPG, heparan sulfate proteoglycan; KSPG, keratan sulfate proteoglycan; PGs, proteoglycans; SAP, serum amyloid P component; SB12, lauryl sulfobetain; SDS, sodium dodecyl sulfate; SLRPs, small leucine rich PGs; TFE, 2,2,2-trifluoroethanol; ThT, thioflavin T; T×100, triton X-100.

AA, amyloid protein A; AApoAII, apolipoprotein A-II-related murine senile; Aβ, amyloid β-peptide; Aβ₂M, β₂-microglobulin-related; AIAPP, islet amyloid polypeptide (amylin)-related; AL, immunoglobulin light chain-related; apoE, apolipoprotein E; apoSAA, serum amyloid A; β₂-m, β₂-microglobulin; CD, circular dichroism; CMC, critical micelle concentration; CS, chondroitin sulfate; CSA, chondroitin sulfate A; CSC, chondroitin sulfate C; DS, dermatan sulfate; DTAC, dodecyl trimethyl ammonium chloride; GAGs, glycosaminoglycans; GM1, GM1 ganglioside; HA, hyaluronic acid; HS, heparan sulfate; HSPG, heparan sulfate proteoglycan; KSPG, keratan sulfate proteoglycan; PGs, proteoglycans; SAP, serum amyloid P component; SB12, lauryl sulfobetain; SDS, sodium dodecyl sulfate; SLRPs, small leucine rich PGs; TFE, 2,2,2-trifluoroethanol; ThT, thioflavin T; T×100, triton X-100.