Microglia are immune system cells associated with senile plaques containing beta-amyloid (Abeta) in Alzheimer's disease. Although microglia are an integral part of senile plaques, their role in the development of Alzheimer's disease is not known. Because microglia are phagocytic cells, it has been suggested that microglia may function as plaque-attacking scavenger cells. Microglia bind and internalize microaggregates of Abeta that resemble those present in dense Alzheimer's disease plaques. In this study, we compared the degradation by microglia of Abeta microaggregates with the degradation of two other proteins, acetylated low density lipoprotein and alpha2-macroglobulin. We found that the majority of the internalized Abeta in microaggregates was undegraded 72 h after uptake, whereas 70-80% of internalized acetylated low density lipoprotein or alpha2-macroglobulin was degraded and released from cells in trichloroacetic acid-soluble form after 4 h. In the continued presence of fluorescent Abeta microaggregates for 4 days, microglia took up huge amounts of Abeta and became engorged with undigested material. These data suggest that microglia can slowly degrade limited amounts of Abeta plaque material, but the degradation mechanisms can be overwhelmed by larger amounts of Abeta.