While multiple conformations of the abnormal prion protein (PrPSc) are thought to encipher prion strain diversity, how they feature in the variable incubation periods observed upon experimental transmission into mice is currently unknown. In order to investigate the natural diversity of sheep scrapie agent, our laboratory has developed a new experimental model consisting of transgenic mice overexpressing the VRQ allele of sheep prion protein (tg338 line). Among 6 potential groups of natural scrapie strains, we have presently stabilised 4 strains that have been biologically cloned and shown to produce stable and distinct phenotypes, based on the incubation time (from 60 to ∼200 days), the molecular profile of PrPSc and its regional distribution in the brain. Moreover these scrapie strains differ in their capacity to replicate in peripheral tissues, such as spleen. For each of these strains, we have examined i) the kinetics of PrPSc accumulation in both brain and spleen, ii) the sensitivity of PrPSc to degradation by either digesting the protein with proteinase K or pepsin in an vitro assay or in vivo by exposing brain homogenates containing PrPP Sc to primary cultures of macrophages, iii) the resistance to denaturation with increasing concentration of guanidine-HCl. These data will be presented and their possible significance in term of strain biology will be discussed.