Soluble Amyloid-beta Aggregates from Human Alzheimer's Disease Brains

Soluble amyloid-beta (A beta) aggregates likely contribute substantially to the dementia that characterizes Alzheimer's disease. However, despite intensive study of in vitro preparations and animal models, little is known about the characteristics of soluble A beta aggregates in the human Alzheimer's disease brain. Here we present a new method for extracting soluble A beta aggregates from human brains, separating them from insoluble aggregates and A beta monomers using differential ultracentrifugation, and purifying them >6000 fold by dual antibody immunoprecipitation. The method resulted in <40% loss of starting material, no detectible ex vivo aggregation of monomeric A beta, and no apparent ex vivo alterations in soluble aggregate sizes. By immunoelectron microscopy, soluble A beta aggregates typically appear as clusters of 10-20 nanometer diameter ovoid structures with 2-3 amino-terminal A beta antibody binding sites, distinct from previously characterized structures. This approach may facilitate investigation into the characteristics of native soluble A beta aggregates, and deepen our understanding of Alzheimer's dementia.