Aggregated amyloid peptides (AP), major components of senile plaques, have been considered to play a very important and crucial role in the development and neuro-pathogenesis of Alzheimer's disease (AD). In the present in vitro study the synergistic effects of Pb 2+ , a heavy metal, and AP on the human neuroblastoma SH-SY5Y cells were investigated. The cells treated with Pb 2+ (0.01-10 οM) alone exhibited a significant decrease in viability and IC 50 was 5 οM. A similar decrease in viability was also observed when the cells were exposed to AP, AΞ²1-40 (20-120 οM) and AΞ²25-35 (2.5-15 οM) for 48 hrs. The IC 50 values were 60 οM and 7.5 οM for AΞ²1-40 and AΞ²25-35 respectively. To assess the synergistic effects the cells were exposed to IC 50 of both AP and Pb 2+ , which resulted in further reduction of the viability. The study was extended to determine the lactate dehydrogenase (LDH) release to assess the cytotoxic effects, 8-isoprostane for extent of oxidative damage, COX 1 and 2 for inflammation related changes, p53 protein for DNA damage and protein kinases A and C for signal transduction. The data suggest that the toxic effects of AP were most potent in the presence of Pb 2+ , resulting in an aggravated clinical pathological condition. This could be attributed to the oxidative stress, inflammation neuronal apoptosis and an alteration in the activities of the signaling enzymes.