Ubiquitinated granular structures and initial neurofibrillary changes in the human brain

Ubiquitin-positive dots and granular structures from insular, temporopolar, hippocampal and parahippocampal cortices of nondemented and Alzheimer's disease patients have been studied with both light and electron microscopes. The relationship of both types of ubiquitin-positive elements with pretangle neurons and neurofibrillary tangles has been analyzed by comparing adjacent or nearly adjacent sections immunostained for either ubiquitin or an antibody that recognizes hyperphosphorylated tau protein (AT-8). Moreover, a double protocol with both antibodies was used in order to obtain double-stained sections. The presence of ubiquitin-positive dots and granular structures precedes the appearance of pretangle neurons in the youngest cases. In aged and Alzheimer disease cases, both types of ubiquitin-positive elements decrease in number as pretangle neurons are replaced by mature and ghost tangles. Ultrastructurally, dots and granular structures appear to be degenerating neuronal processes and/or terminals. Our results suggest that the degeneration of these processes and/or terminals might be related with the initiation of neurofibrillary degeneration.