Mechanism of PrP-amyloid formation in mice without transmissible spongiform encephalopathy

Gerstmann-Sträussler-Scheinker (GSS) P102L disease is a familial form of a transmissible spongiform encephalopathy (TSE) that can present with or without vacuolation of neuropil. Inefficient disease transmission into 101LL transgenic mice was previously observed from GSS P102L without vacuolation. However, several aged, healthy mice had large plaques composed of abnormal prion protein (PrP(d)). Here we perform the ultrastructural characterization of such plaques and compare them with PrP(d) aggregates found in TSE caused by an infectious mechanism. PrP(d) plaques in 101LL mice varied in maturity, with some being composed of deposits without visible amyloid fibrils. PrP(d) was present on cell membranes in the vicinity of all types of plaques. In contrast to the unicentric plaques seen in infectious murine scrapie, the plaques seen in the current model were multicentric and were initiated by protofibrillar forms of PrP(d) situated on oligodendroglia, astrocytes and neuritic cell membranes. We speculate that the initial conversion process leading to plaque formation begins with membrane-bound PrP(C) but that subsequent fibrillization does not require membrane attachment. We also observed that the membrane alterations consistently seen in murine scrapie and other infectious TSEs were not present in 101LL mice with plaques, suggesting differences in the pathogenesis of these conditions.