Ultrastructure of the cells forming amyloid fibers in Alzheimer disease and scrapie.

Ultrastructural, three-dimensional reconstruction of cells surrounding the amyloid star in classical plaques in Alzheimer disease (AD) and histochemical studies of the cells associated with the deposits of amyloid fibers in scrapie were carried out. These studies showed that in both diseases, the fibers appear within the smooth endoplasmic reticulum (ER) and infoldings of cytoplasmic membranes of microglia/macrophages. Additional information about the site of formation of the amyloid fibers derives from histochemical studies of the localization of nucleoside diphosphatase (NDPase) activity. In normal microglia, this enzyme is associated with smooth ER and cell membranes. In the cells that form amyloid fibers, the NDPase activity is associated with the newly formed amyloid fibers within the distended cisternae of ER and the finger-like cytoplasmic projections. In the center of the amyloid star, the NDPase activity disappears. The presence of NDPase-positive amyloid fibers in the same location, where the enzyme is found in non-amyloid-forming cells, further supports our conclusion that the microglia/macrophages are the source of amyloid deposits. These studies also show that in spite of the differences in the proteins that produce the amyloid fibers in AD and scrapie, in both diseases, the microglia/macrophages play a key role in amyloid formation.