Prion clearance in bigenic mice

The clearance of prions from the brain was investigated in bigenic mice designated Tg(tTA: PrP+/0)3, in which expression of the cellular prion protein (PrPC) was regulated by oral doxycycline administration. With suppression of PrPC expression, the incubation time for RML prions was prolonged almost threefold from similar to 150 to similar to 430 days, To determine the clearance rate of disease-causing PrPSc, bigenic mice were given oral doxycycline beginning 98 days after inoculation with RML prions and sacrificed at various time points over the subsequent 56 days. The half-life (t(1/2)) for PrPSc was similar to 1(.)5 days in mouse brain, in reasonable agreement with the apparent t(1/2) of 30 In that was determined in a separate study for scrapie-infected mouse neuroblastoma (ScN2a) cells in culture. Both protease-sensitive and -resistant conformers of PrPSc were cleared at the same rate. The t(1/2) value for PrPC clearance from brain was similar to 18 h, which was considerably longer than the t(1/2) of 5 h found in ScN2a cells. The capability of the brain to clear prions; raises the possibility that PrPSc is normally made at low levels and continually cleared, and that PrPSc may have a function in cellular metabolism. Moreover, these bigenic mice make it possible to determine both components of PrPSc accumulation, i.e. the rates of formation and clearance, for various strains of prions exhibiting different incubation times.