IDENTIFICATION OF THE END-STAGE OF SCRAPIE USING INFECTED NEURAL GRAFTS

Although the formal pathogenesis of spongiform encephalopathies has be en described in detail, it is not known whether the infectious agent t argets primarily neurons, glial cells, or both, To address this questi on, we have transplanted transgenic embryonic neural tissue overexpres sing PrPc into the forebrain of Prnp -knockout mice, and infected it w ith scrapie prions, After infection, grafts developed severe spongifor m encephalopathy. As the infected hosts were not clinically affected, we were able to prolong the experiment and to assess changes in the gr aft over periods of time, which vastly exceeded the normal life span o f scrapie-infected mice, Sequential contrast-enhanced magnetic resonan ce imaging (MRI) revealed progressive impairment of blood-brain barrie r properties in infected grafts, However, loss of astrocytes was not o bserved, Subtotal neuronal loss occurred during the progression of the disease in the grafts, reactive astrocytes persisted until the termin al stage of disease, We conclude that scrapie encephalopathy primarily leads to neuronal death, while degeneration of astrocytes does not oc cur, Functional impairment of the blood-brain barrier suggests involve ment of astrocytes and endothelial cells in the pathological process.