Brain lesions in Creutzfeldt-Jakob disease (CJD) include spongiform change, neuronal loss, amyloid plaques, astrogliosis and microglial activation. Microglia are thought to play a key role in prion-induced neurodegeneration. However, the intermediate molecules supporting relationships between neurons and microglia are still unknown. Chromogranins (Cg) are soluble glycophosphoproteins that can activate microglial cells leading to a neurotoxic phenotype. The immunoreactive patterns of CgA and CgB were investigated in CJD and compared to those observed in Alzheimer's disease. We found that CgB, but not CgA, immunoreactivity was selectively associated with prion protein deposits, whereas CgA was only seen in Abeta plaques. This suggests a specific influence of the constitutive amyloid protein on chromogranin secretion and a role of CgB in the CJD neurodegenerative process.