INHIBITION OF SCRAPIE-ASSOCIATED PRP ACCUMULATION - PROBING THE ROLE OF GLYCOSAMINOGLYCANS IN AMYLOIDOGENESIS

Accumulation of an abnormal, protease-resistant form of an endogenous protein, PrP, is a characteristic feature of scrapie and related trans missible spongiform encephalopathies. This abnormal isoform is also pr esent in the amyloid plaques that are often observed in these diseases . In mouse neuroblastoma cells persistently infected with scrapie, the abnormal protease-resistant isoform of PrP is derived from an operati onally normal protease-sensitive precursor. Conversion of PrP to the p rotease-resistant state occurs either on the plasma membrane or along an endocytic pathway by an unknown mechanism. Inhibitors of protease-r esistant PrP accumulation have been identified, and these include the amyloid-binding dye Congo red and certain sulfated glycans. The simila rity of these compounds to sulfated glycosaminoglycans, which are comp onents of all natural amyloids, has led to the hypothesis that the inh ibitors act by competitively blocking an interaction between endogenou s glycosaminoglycan(s) and PrP that is critical for amyloidogenic PrP accumulation. The proven prophylactic effect of these sulfated glycans in animal models of scrapie suggests that they represent a group of c ompounds that might interfere with the pathogenic formation of amyloid in a variety of diseases, such as Alzheimer's disease.