Role of α2‐macroglobulin in regulating amyloid β‐protein neurotoxicity: protective or detrimental factor?

α2‐Macroglobulin (α2M) has been identified as a carrier protein for β‐amyloid (Aβ) decreasing fibril formation and affecting the neurotoxicity of this peptide. The α2‐macroglobulin receptor/low density lipoprotein receptor related protein (LRP) is involved in the internalization and degradation of the α2M/Aβ complexes and its impairment has been reported to occur in Alzheimer's disease. Previous studies have shown α2M to determine an enhancement or a reduction of Aβ toxicity in different culture systems. In order to clarify the role of α2M in Aβ neurotoxicity, we challenged human neuroblastoma cell lines with activated α2M in combination with Aβ. Our results show that in neuroblastoma cells expressing high levels of LRP, the administration of activated α2M protects the cells from Aβ neurotoxicity. Conversely, when this receptor is not present α2M 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 α2M resulted to be protective against Aβ‐induced neurotoxicity. By means of recombinant proteins we ascribed the neurotoxic activity of α2M 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 α2M regulated by the expression of its receptor LRP.