Neurodegenerative diseases such as Alzheimer's, Parkinson's and the transmissible spongiform encephalopathies (TSEs) are characterized by abnormal protein deposits, often with large amyloid fibrils. However, questions have arisen as to whether such fibrils or smaller subfibrillar oligomers are the prime causes of disease. Abnormal deposits in TSEs are rich in PrP(res), a protease-resistant form of the PrP protein with the ability to convert the normal, protease-sensitive form of the protein (PrP(sen)) into PrP(res) (ref. 3). TSEs can be transmitted between organisms by an enigmatic agent (prion) that contains PrP(res) (refs 4 and 5). To evaluate systematically the relationship between infectivity, converting activity and the size of various PrP(res)-containing aggregates, PrP(res) was partially disaggregated, fractionated by size and analysed by light scattering and non-denaturing gel electrophoresis. Our analyses revealed that with respect to PrP content, infectivity and converting activity peaked markedly in 17-27-nm (300-600 kDa) particles, whereas these activities were substantially lower in large fibrils and virtually absent in oligomers of < or =5 PrP molecules. These results suggest that non-fibrillar particles, with masses equivalent to 14-28 PrP molecules, are the most efficient initiators of TSE disease.

In prion and Alzheimer's diseases, the roles played by amyloid versus nonamyloid deposits in brain damage remain unresolved. In scrapie-infected transgenic mice expressing prion protein (PrP) lacking the glycosylphosphatidylinositol (GPI) membrane anchor, abnormal protease-resistant PrPres was deposited as amyloid plaques, rather than the usual nonamyloid form of PrPres. Although PrPres amyloid plaques induced brain damage reminiscent of Alzheimer's disease, clinical manifestations were minimal. In contrast, combined expression of anchorless and wild-type PrP produced accelerated clinical scrapie. Thus, the PrP GPI anchor may play a role in the pathogenesis of prion diseases.

A better understanding of the infectious process in scrapie was sought by studying the temporal distribution of virus in naturally infected Suffolk sheep. Virus was detected (by mouse inoculation) first in lymphatic tissues and intestine of clinically normal lambs (age, 10-14 months). Titers were generally low. Infection of the central nervous system was first detected in a 25-month-old clinically normal sheep whose nonneural tissues had moderate amounts of virus. In sheep affected with scrapie, similar amounts in nonneural tissues accompanied high concentrations in the central nervous system, notably in sites of severest neurohistologic changes. No virus was found in clinically normal high-risk sheep 54 to 104 months old. The early appearance of virus in tonsil, retropharyngeal and mesenteric-portal lymph nodes, and intestine suggests that primary infection occurs by way of the alimentary tract, either prenatally from virus in amniotic fluid or postnatally from virus in a contaminated environment.