beta(2)-microglobulin (beta(2)m) deposits as amyloid in dialysis-related amyloidosis (DRA), predominantly ill joints. The molecular mechanisms underlying the amyloidogenicity Of beta(2)m are still largely unknown. In vitro, acidic conditions, pH < 4.5, induce amyloid fibrillation of native beta(2)m within several days. Here, we show that amyloid fibrils are generated in less than an hour when a cleavage variant of beta(2)m-found in the circulation of many dialysis patients-is exposed to pH levels (pH 6.6) occurring in joints during inflammation. Aggregation and fibrillation, including seeding effects with intact, native beta(2)m were studied by Thioflavin T fluorescence spectroscopy, turbidimetry, capillary electrophoresis, and electron microscopy. We conclude that a biologically relevant variant of beta(2)m is amyloidogenic it slightly acidic pH. Also, only a very small amount of preformed fibrils of this variant is required to induce fibrillation of native beta(2)m. This may explain the apparent lack of detectable amounts of the variant beta(2)m in extracts of amyloid from DRA patients. (C) 2009 Elsevier Inc. All rights reserved.