Neuropathological features of transmissible spongiform encephalopathies. Histology and immunohistochemical analysis of frontal cortex samples of the brain of a patient who died of noncerebral causes (upper row) and a patient suffering from Creutzfeldt-Jakob disease (CJD) (lower row). Brain sections were stained with hematoxylin-eosin (HE, left panels), with antibodies against glial fibrillary acidic protein (GFAP, middle panels), and with antibodies against the prion protein (PrP, right panels). Neuronal loss and prominent spongiosis are visible in the HE stain. Strong proliferation of reactive astrocytes (gliosis) and perivacuolar PrP deposits are detectable in the GFAP and PrP immunostains of the CJD brain samples. 

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... all the unresolved problems, a number of important properties of the infectious agent can be studied, even in the absence of ultimate certainty about its true physical nature. Perhaps the most obvious ques- tion regards what accounts for the exquisite propensity of prions to damage the central nervous system (CNS), the only part of the body undergoing histopathologi- cally and clinically detectable degeneration (Figure 3). Cellular models of prion disease may prove very useful for addressing this question. However, prions replicate inefficiently in most established cell lines. A large num- ber of studies have been performed with a synthetic pep- tide obtained from the central region of the PrP C mole- cule, which has been shown to spontaneously assemble into amyloid-like structures. Interestingly, this peptide can elicit in vitro many reactions of brain cells that resemble those seen in vivo during the late stages of prion disease: activation of microglia cells, stimulation of intermediate filament production by astrocytes, and even death of neurons, which appears to depend on the presence of the normal prion protein in target cells. 47,48 Despite the amount of information that has been accrued, all of these studies suffer from the fundamental problem that it is not clear whether the phenomenon observed in conjunction with exposure of cells to this small amyloidogenic peptide bear much relevance to what is happening in vivo during the course of prion replication-a process that may arguably be very dif- ferent. Moreover, some of the published data have recently been challenged. 49 In order to ask the simple question of whether cerebral accumulation of PrP Sc in the extracellular space suffices to damage nerve cells, we have undertaken fetal neuro- ectodermal transplantation experiments. 50 Histological analysis of PrP-deficient mice that had been grafted with brain cells derived from transgenic mice overexpress- ing PrP C and subsequently infected with prions indicated that pathology is confined to the regions of the brain that express PrP C . In the surrounding PrP-deficient brain, no pathological changes could be detected even though substantial accumulations of pathological PrP Sc occurred. 50 While the interpretation of this experiment is liable to certain caveats (most notably the possibility that a threshold concentration of PrP Sc is needed for induction of neurodegeneration and is not attained out- side the grafted tissue), it is difficult to avoid the con- clusion that the neuronal cytotoxicity of PrP Sc is depen- dent on the expression of cellular PrP C by target cells. Why should that be? Perhaps PrP C acts as a receptor for PrP Sc . However, it has never been possible to demon- strate an affinity between these two moieties. Alterna- tively, the conversion process of PrP C into PrP Sc itself, rather than exposure to the disease-associated prion protein, may constitute the primary deleterious ...