The presence of the α 2 macroglobulin receptor/low density lipoprotein receptor-related protein (α 2 Mr/LRP) and its ligands α 2 macroglobulin (α 2 M), apoliprotein E, and plasminogen activators was detected in senile plaques of Alzheimer's disease (AD). To explore a possible role of α 2 M in neurodegenerative processes occurring in AD, we analyzed the effect of α 2 M on Aβ 25–35-induced neurotoxicity. Treatment of LAN5 human neuroblastoma cells with 10 μM β-amyloid peptide fragment 25–35 (Aβ 25–35) for 72 h resulted in a 50% decrease in cell viability as determined by MTT incorporation and cell counts. The addition of α 2 M to the culture medium of these cells did not determine any effect, but when the activated form α 2 M* was used a dose-dependent decrease in cell viability was observed, the maximum effect being reached at 140 and 280 nM. Moreover, treatment of LAN5 cells with α 2 M* in combination with Aβ 25–35 increased the neurotoxicity of the amyloid peptide by 25%. This neurotoxic effect of α 2 M* seems to be related to its capability to bind and inactivate TGFβ in the culture medium, since it was mimicked by a TGFβ neutralizing antibody. A possible involvement of receptor-mediated endocytosis was ruled out, since α 2 M receptor is not present on LAN5, as revealed by RT-PCR and Western blotting experiments.The presence of α 2 M* in amyloid deposits of Alzheimer's disease has been recently reported and a possible impairment of LRP internalization processes has been hypothesized. Our data suggest that the local accumulation of α 2 M* in AD plaques may increase Aβ 25–35-induced neurotoxicity by neutralizing TGFβ-mediated neuroprotective mechanisms.