Intrinsic resistance of oligodendrocytes to prion infection

Within the CNS, the normal form of cellular prion protein (PrPC) is expressed on neurons, oligodendrocytes, and astrocytes. The contribution of these cell types to prion replication and pathogenesis is unclear. To assess the role of oligodendrocytes, we expressed PrPC under the control of the myelin basic protein (MBP) promoter in mice lacking endogenous PrPC. PrPC was detected in oligodendrocytes and Schwann cells but not in neurons and astrocytes. MBP - PrP mice never developed scrapie after intracerebral, intraperitoneal, or intraocular challenge with scrapie prions. Transgenic brains did not contain protease-resistant prion protein and did not transmit scrapie when inoculated into PrPC-overexpressing indicator mice. To investigate whether prion spread within the CNS depends on oligodendrocytic PrPC, we implanted PrPC-overexpressing neuroectodermal grafts into MBP - PrP brains. After intraocular prion inoculation, none of the grafts showed spongiform encephalopathy or prion infectivity. Hence oligodendrocytes do not support cell-autonomous prion replication, establishment of subclinical disease, and neural spread of prions. Prion resistance sets oligodendrocytes aside from both neurons and astrocytes.