A distinct subfraction of Aβ is responsible for the high-affinity Pittsburgh compound B-binding site in Alzheimer's disease brain

The positron emission tomography (PET) ligand C-11-labeled Pittsburgh compound B (PIB) is used to image -amyloid (A) deposits in the brains of living subjects with the intent of detecting early stages of Alzheimer's disease (AD). However, deposits of human-sequence A in amyloid precursor protein transgenic mice and non-human primates bind very little PIB. The high stoichiometry of PIB:A binding in human AD suggests that the PIB-binding site may represent a particularly pathogenic entity and/or report local pathologic conditions. In this study, H-3-PIB was employed to track purification of the PIB-binding site in >90% yield from frontal cortical tissue of autopsy-diagnosed AD subjects. The purified PIB-binding site comprises a distinct, highly insoluble subfraction of the A in AD brain with low buoyant density because of the sodium dodecyl sulfate-resistant association with a limited subset of brain proteins and lipids with physical properties similar to lipid rafts and to a ganglioside:A complex in AD and Down syndrome brain. Both the protein and lipid components are required for PIB binding. Elucidation of human-specific biological components and pathways will be important in guiding improvement of the animal models for AD and in identifying new potential therapeutic avenues.