β2-microglobulin is potentially neurotoxic, but the blood brain barrier is likely to protect the brain from its toxicity

Background. In dialysis-related amyloidosis, β2microglobulin accumulates as amyloid fibrils preferentially around bones and tendons provoking osteoarthritis. In addition to the pathologic role played by the amyloid fibrils, it can be speculated that a pathogenic role is also played by the high concentrations of soluble β2-microglobulin because it is toxic for certain cell lines like HL60 and mitogen for other cells such as the osteoclasts. The discovery that β2-microglobulin can influence the biology of certain cells may lead to the assumption that it might affect neuronal cells that are quite sensitive to amyloidogenic proteins in the oligomeric state. Such a concern might be supported by clinical evidence that haemodialysis is associated with the risk of a cognitive impairment. Methods. The cytotoxicity of β2-microglobulin on the SHSY5Y neuroblastoma cells was assayed by the MTT test. The β2-microglobulin concentration was determined in the cerebrospinal fluid of four different patients by means of immunonephelometry and western blot. Results. Oligomeric β2-microglobulin is cytotoxic for the SH-SY5Y cells at a concentration that can be easily reached in the plasma of patients on haemodialysis. However, theβ2microglobulin concentration, measured in the cerebrospinal fluid of a haemodialysis patient, appears to be independent of its plasma concentration and is maintained under the lower limit of cytotoxicity we have determined in the cell culture. Conclusions. Although β2-microglobulin is potentially neurotoxic, it is unlikely that this protein plays a role in the pathophysiology of cognitive impairment observed in haemodialysis patients due to the protective effect of the blood brain barrier that maintains a low concentration of β2-microglobulin in the cerebrospinal fluid. Correspondence and offprint requests to: Vittorio Bellotti, Dipartimento di Biochimica, via Taramelli 3b, 27100 Pavia, Italy. Tel:+39-0382987932; Fax: +39-0382423108; E-mail: [email protected]