The putative role of alpha-1-antitrypsin in the disaggregation of amyloid lambda fibrils.

Abstract

BACKGROUND AND OBJECTIVES: Interactions between hydrophobic compounds like cholesterol and lithocholic acid and alpha-1-antitrypsin (alpha-1-AT) have previously been described. We studied the putative interaction between alpha-1-AT and the insoluble, hydrophobic, beta-pleated sheet, light-chain-derived fibrils that predominate the tissue deposits in primary immunocytic (AL) related amyloidosis. SUBJECTS AND METHODS: Amyloid fibrils were isolated from two cases with lambda and two cases with kappa AL amyloidosis. RESULTS: The lambda fibrils could be completely disaggregated (as shown by light and electron microscopy and Congo red uptake) by alpha-1-AT added in the molar ratio 1:5, whereas fibrils with predominantly kappa chains remained unaffected. The lambda-chain interaction was accompanied by characteristic changes of the physicochemical and biological properties of alpha-1-AT apparent in an increased thermal stability and loss of elastase-inhibitory activity. These findings are compatible with a transition of alpha-1-AT from a native, stressed conformation to a relaxed form. CONCLUSIONS: Disaggregation of lambda AL amyloid fibrils can be achieved by addition of alpha-1-AT. The findings may have therapeutic implications in primary amyloidosis.