A β2-microglobulin cleavage variant fibrillates at near-physiological pH

β2-microglobulin (β2m) deposits as amyloid in dialysis-related amyloidosis (DRA), predominantly in joints. The molecular mechanisms underlying the amyloidogenicity of β2m are still largely unknown. In vitro, acidic conditions, pH < 4.5, induce amyloid fibrillation of native β2m within several days. Here, we show that amyloid fibrils are generated in less than an hour when a cleavage variant of β2m—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 β2m were studied by Thioflavin T fluorescence spectroscopy, turbidimetry, capillary electrophoresis, and electron microscopy. We conclude that a biologically relevant variant of β2m is amyloidogenic at slightly acidic pH. Also, only a very small amount of preformed fibrils of this variant is required to induce fibrillation of native β2m. This may explain the apparent lack of detectable amounts of the variant β2m in extracts of amyloid from DRA patients.