A consistent rat model for the study of the consequences of congophilic and fibrillar Ap-amyloid in brain has been developed. One hundred percent of animals receiving infusions of synthetic p-amyloid protein (Afl l-40) plus a specific heparan sulfate proteoglycan (HSPC) for 1 week or 7 weeks (following 2 week infusions) demonstrated Congo red and thioflavin S-positive deposits adjacent to the infusion site. Extracellular amyloid fibrils were identified by electron microscopy and were immunogold decorated with Afl antibody. Significant increases in Congo red staining were observed in animals infused with AP plus HSPG versus those infused with only A& Infusion of AP alone was variable with respect to congophilic amyloid persistence, which occurred in 50% of animals and only when endogenous HSPGs accumulated at Afl deposition sites. By 7 weeks, only animals infused with Aj3 plus HSPC demonstrated compaction of the Congo red material from amorphous, wispy deposits (at 1 week) to stellate deposits resembling a Maltese cross. These spherical amyloid deposits were very similar to Congo red-stained amyloid plaques in human Alzheimer’s disease brain, and in vitro data suggest that they were probably formed in vivo following interactions with endogenous brain components.