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