ALPHA(2)-MACROGLOBULIN ATTENUATES BETA-AMYLOID PEPTIDE-1-40 FIBRIL FORMATION AND ASSOCIATED NEUROTOXICITY OF CULTURED FETAL-RAT CORTICAL-NEURONS

beta-Amyloid peptides (A beta) are deposited in an aggregated fibrilla r form in both diffuse and senile plaques in the brains of patients wi th Alzheimer's disease. The neurotoxicity of A beta in cultured neuron s is dependent on its aggregation state, but the factors contributing to aggregation and fibril formation are poorly understood. In the pres ent study, we investigated whether alpha(2)-macroglobulin (alpha(2)M), a protein present in neuritic plaques and elevated in Alzheimer's dis ease brain, is a potential regulatory factor for A beta fibril formati on. Previous studies in our laboratory have shown that alpha(2)M is an A beta binding protein. We now report that, in contrast to another pl aque-associated protein, alpha(1)-antichymotrypsin, alpha 2M coincubat ed with A beta significantly reduces aggregation and fibril formation in vitro. Additionally, cultured fetal rat cortical neurons are less v ulnerable to the toxic actions of aged A beta following pretreatment w ith alpha(2)M. We postulate that alpha(2)M is able to maintain A beta in a soluble state, preventing fibril formation and associated neuroto xicity.