In order to investigate the cellular basis of human astrogliosis, we have selected the cerebellar cortex because it provides a relatively simple and geometrical organization of both neuronal and glial populations. A pathological system with severe and progressive loss of granule cells was studied: the ataxic form of Creutzfeldt-Jakob disease, where the tissue geometry is minimally disturbed. The quantitative study revealed a drastic reduction in the numerical density of granule cells in the Creutzfeldt-Jakob disease cerebellum, and a significant increase in the numerical density of astrocytes. Karyometric analysis showed that the nuclear area was significantly greater in reactive astroglial cells than in normal astroglia. Glial fibrillary acidic protein immunocytochemistry revealed astroglial hypertrophy, but the geometry and spatial domains of astroglial subtypes were strictly preserved. Vimentin expression was detected in Bergmann glia and in certain astrocytes of the granular layer. Ultrastructural analysis showed that reactive astroglia had large nuclei, with expanded interchromatinic regions which contained clusters of interchromatin granules and nuclear bodies, and prominent reticulate nucleoli. In the cytoplasm, hypertrophied bundles of intermediate filaments were observed, some of them associated with the nuclear envelope. Numerous adhering and gap junctions were also found among reactive astroglial cells. Perivascular glial processes showed a terminal web of intermediate filaments and a conspicuous plasmalemmal undercoat. Interendothelial tight junctions were preserved. Our results suggest that the severe loss of granule cells induces a highly ordered astroglial response which tends to preserve the geometry of the astroglial scaffold, the domains of each astroglial subtype, the neuronal microenvironmental conditions and the efficiency of the blood brain barrier, in order to promote neuron survival.