Role of alpha(2)-macroglobulin in regulating amyloid beta-protein neurotoxicity: protective or detrimental factor?

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