Beta-amyloid peptides (A beta) are deposited in an aggregated fibrillar form in both diffuse and senile plaques in the brains of patients with Alzheimer's disease. The neurotoxicity of A beta in cultured neurons is dependent on its aggregation state, but the factors contributing to aggregation and fibril formation are poorly understood. In the present study, we investigated whether alpha2-macroglobulin (alpha2M), a protein present in neuritic plaques and elevated in Alzheimer's disease brain, is a potential regulatory factor for A beta fibril formation. Previous studies in our laboratory have shown that alpha2M is an A beta binding protein. We now report that, in contrast to another plaque-associated protein, alpha1-antichymotrypsin, alpha2M coincubated with A beta significantly reduces aggregation and fibril formation in vitro. Additionally, cultured fetal rat cortical neurons are less vulnerable to the toxic actions of aged A beta following pretreatment with alpha2M. We postulate that alpha2M is able to maintain A beta in a soluble state, preventing fibril formation and associated neurotoxicity.