Tissue plasminogen activator (tPA) is expressed by many types of neurons in the developing and adult rodent brain. We have now mapped tPA transcripts and protein in the human central nervous system using tissue arrays and find widespread expression, in particular in neocortical mantle, thalamus, amygdala, and hippocampal pyramidal neurons. The abundant presence of tPA protein in cellular vesicles implies that its acute release, e.g. upon ischaemic stroke or trauma, could play a role in neuronal damage. We also found in patients with multiple sclerosis (MS), and to a lesser extent patients with leukaemia and encephalitis, prominently elevated tPA activity in the cerebrospinal fluid and in MS in neurons in the proximity of areas of demyelination elevated tPA mRNA and antigen levels. In addition, we observed up-regulation of tPA expression in a mouse model of MS, experimental autoimmune encephalomyelitis. Accumulating evidence implies roles for tPA in normal neural function, as well as in neurodestructive processes in humans, such as occur in MS and brain tumours and warrant further studies on expression of tPA and its regulatory molecules in neurodegenerative diseases.