Selective neuronal targeting in prion disease.

The pattern of scrapie prion protein (PrP(Sc)) accumulation in the brain is different for each prion strain. We tested whether the PrP(Sc) deposition pattern is influenced by the Asn-linked oligosaccharides of PrP(C) in transgenic mice. Deletion of the first oligosaccharide altered PrP(C) trafficking and prevented infection with two prion strains. Deletion of the second did not alter PrP(C) trafficking, permitted infection with one prion strain, and had a profound effect on the PrP(Sc) deposition pattern. Our data raise the possibility that glycosylation can modify the conformation of PrP(C). Glycosylation could affect the affinity of PrP(C) for a particular conformer of PrP(Sc), thereby determining the rate of nascent PrP(Sc) formation and the specific patterns of PrP(Sc) deposition.

Aberrant induction of neuropeptide Y mRNA in hippocampal CA3 pyramidal neurones in scrapie-infected mice.

The neurochemical alterations preceding neurological dysfunction and neuronal death in prion diseases are not well characterized. Here we examined, using in situ hybridization histochemistry, the expression of neuropeptide Y (NPY), an inducible and abundant neuropeptide in mammalian brain with known neuroregulatory functions, and glial fibrillary acidic protein (GFAP), a marker for astroglial activation, in the hippocampus at different time points following intracerebral prion inoculation in male CD-1 mice. Between 110 and 140 days postinoculation NPY mRNA expression was specifically up-regulated in CA3 pyramidal neurones, whereas expression of NPY in hilar neurones remained unaltered. Up-regulation of GFAP mRNA was observed in the CA1 stratum radiatum at 60 days, and spread throughout the hippocampus, cortex and thalamus between 110 and 140 days, suggesting early accumulation of scrapie prion protein in these regions. The clinical symptoms were first manifested 120 days postinoculation. Aberrant induction of NPY mRNA in the hippocampal CA3 pyramidal neurones preceded the onset of neurological symptoms, and may be involved in the regulation of glutamate release at the Schaffer collateral-CA1 synapses in scrapie-infected mice.

Scrapie in mice deficient in apolipoprotein E or glial fibrillary acidic protein.

In the prion diseases, extensive reactive gliosis is often found to be out of proportion to the degree of apparent neuronal damage. To evaluate the role of astrocytic gliosis in experimental scrapie of the mouse, we inoculated mice deficient in apolipoprotein E (apoE) or the glial fibrillary acidic protein (GFAP) with mouse prions. The expression of both apoE and GFAP in astrocytes increases as part of the reactive gliosis that accompanies scrapie. Null mice deficient in either apoE or GFAP inoculated with prions exhibited incubation times indistinguishable from untargeted control mice. The level of PrPSc and its regional deposition in the brains of ill mice deficient in either protein were also similar to control mice. Our findings demonstrate that neither apoE nor GFAP participates in the pathogenesis of the disease or in the production of PrPSc.