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(American Journal of Pathology. 2005;166:287-294.)
© 2005 American Society for Investigative Pathology

Subcellular Localization of Disease-Associated Prion Protein in the Human Brain

Gábor G. Kovács^*, Matthias Preusser^*, Michaela Strohschneider^* and Herbert Budka^*

From the Institute of Neurology, Medical University of Vienna, and Austrian Reference Centre for Human Prion Diseases,^* Vienna, Austria; and the National Institute of Psychiatry and Neurology and Hungarian Reference Centre for Human Prion Diseases, Budapest, Hungary

Disease-associated prion protein (PrP^TSE) deposits in distinct immunostaining patterns in the brain in Creutzfeldt-Jakob disease, including synaptic, extracellular, and cell-associated localizations. After having developed an appropriate pretreatment protocol to enhance immunostaining for PrP^TSE without damaging epitopes of other antigens, we systematically evaluated co-localization patterns of distinct PrP^TSE immunodeposits by confocal laser microscopy, including optical serial sectioning. As shown by quantification, the most prominent co-localization of PrP^TSE is with synaptophysin, but PrP^TSE may also co-deposit with connexin-32, a gap junction-related protein. Furthermore, neuronal cell bodies, dendrites, axons, astrocytes, and microglia harbor granular PrP^TSE deposits. Highly aggregated deposits are focally ubiquitinated. We conclude that PrP^TSE is not exclusively associated with chemical but also with electric synapses, axonal transport may be a relevant route of PrP^TSE spread in the brain, and activated microglia and astrocytes may play a role in PrP^TSE processing, degradation, or removal.

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