Role of α 2 ‐macroglobulin in regulating amyloid β‐protein neurotoxicity: protective or detrimental factor?

α 2 ‐Macroglobulin (α 2 M) has been identified as a carrier protein for β‐amyloid (Aβ) decreasing fibril formation and affecting the neurotoxicity of this peptide. The α 2 ‐macroglobulin receptor/low density lipoprotein receptor related protein (LRP) is involved in the internalization and degradation of the α 2 M/Aβ complexes and its impairment has been reported to occur in Alzheimer's disease. Previous studies have shown α 2 M to determine an enhancement or a reduction of Aβ toxicity in different culture systems. In order to clarify the role of α 2 M in Aβ neurotoxicity, we challenged human neuroblastoma cell lines with activated α 2 M in combination with Aβ. Our results show that in neuroblastoma cells expressing high levels of LRP, the administration of activated α 2 M protects the cells from Aβ neurotoxicity. Conversely, when this receptor is not present α 2 M determines an increase in Aβ toxicity as evaluated by MTT and TUNEL assays. In LRP‐negative cells transfected with the full‐length human LRP, the addition of activated α 2 M resulted to be protective against Aβ‐induced neurotoxicity. By means of recombinant proteins we ascribed the neurotoxic activity of α 2 M to its FP3 fragment which has been previously shown to bind and neutralize transforming growth factor‐β. These studies provide evidence for both a neuroprotective and neurotoxic role of α 2 M regulated by the expression of its receptor LRP.