In order to characterize synaptic involvement in human spongiform encephalopathies, the expression of synaptic vesicle-associated proteins, synaptophysin and synapsin-I, and presynaptic plasma membrane proteins, synaptosomal-associated protein of 25 kDa (SNAP-25) and syntaxin-I, was examined in the brains of four patients who had suffered from sporadic Creutzfeldt-Jakob disease. Nerve cell loss, spongiform degeneration, astrocytosis, and deposition of prion protein (PrP) were observed in the cerebral cortex in every case. Decreased immunoreactivity for synaptophysin, synapsin-I, SNAP-25, and syntaxin-I was observed in the cerebral cortex in every case, thus showing generalized reduction of proteins involved in exocytosis of synaptic vesicles in the brains of patients with spongiform encephalopathy. Upregulation of synaptophysin and SNAP-25, a feature associated with beta A4 deposits in Alzheimer's disease (AD), was not observed in associated with PrP deposition. The present results indicate that synaptic pathology is a major event in spongiform encephalopathy, and suggest that synaptic loss, together with neuron loss and selective involvement of certain populations of local-circuit neurons, as shown in other studies, may account for the dramatic neurological decay and for the main neurological symptoms in patients with CJD.