A non-nuclear isoform of histone H1 is constitutively expressed in neurones. This protein is the major lipopolysaccharide (LPS)-binding protein in the brain. Since the major systemic LPS-binding protein is released in the liver and is an acute phase reactant, we were interested to learn whether this novel CNS histone showed altered expression following neuronal injury. We have therefore examined the changes in the expression of this molecule in acute neuronal injury and in two neurodegenerative pathologies, murine scrapie and Alzheimer's disease. No upregulation or change in H1 staining was observed in acute neurodegeneration induced by the intrastriatal injection of the glutamate antagonist N-methyl d-aspartic acid. In contrast, Western blotting indicated that histone H1 is upregulated in the brains of mice with clinical signs of scrapie. Immunohistochemistry revealed that in the regions of pathology there was increased staining for histone H1 in the neurones and the surrounding neuropil. Cells with an astrocytic appearance were also seen to stain positively for H1 but only in the regions of pathology. Immunofluorescent double staining for glial fibrillary acid protein (GFAP) and histone H1 confirmed that these cells were indeed astrocytes. Alzheimer's disease brain also showed an increase in the neuronal and astrocytic staining but only in regions of pathology. The function of histone in the CNS is unknown but the data presented here demonstrate an upregulation in areas of neuronal degeneration, which indicates that it may be involved in disease pathogenesis.