The origin of the specific heparan sulfate proteoglycan (PG), perlecan, in beta-amyloid protein (Aβ)-containing amyloid deposits in Alzheimer's disease(AD) brain is not known. In the present investigation, we primarily used indirect immunofluorescence methods to identify possible cell candidates of perlecan production in both primary cell cultures, and in a rat infusion model (Neuron 12:219-234, 1994). Double and triple-labelled indirect immunofluorescence was performed on dissociated primary rat septae cultures using specific antibodies for identification of different cell types, and for perlecan core protein. In mixed cultures of both E18 (which contain neurons, astrocytes, microglia, and oligodendrocytes) and P2-3 (devoid of neurons), microglia identified by labeling with OX-42 or anti-ED1 were the only cell type also double labeled with a polyclonal antibody against perlecan core protein. Similar immunolabeling of microglia with the anti-perlecan antibody was also observed in purified cultures of post-natal rat microglia. Western blot analyses of microglial cell layer PGs with the perlecan core protein antibody revealed a - 400 kDa core protein (suggestive of perlecan) following heparitinase digestion. Other lower M r bands were also found implicating either degradation of the 400 kDa core protein or the presence of separate and distinct gene products immunologically related to perlecan. Following a 1-week continuous infusion of Aβ (1-40) into rodent hippocampus, double and triple-labeled immunofluorescent studies revealed perlecan accumulation primarily localized to infiltrating microglia within the Aβ infusion site. These studies suggest that microglia may represent one source of perlecan (or an immunologically related PG), which may be important for the ongoing accumulation of both perlecan and Aβ in the amyloid deposits of AD.