A SEQUENCE OF CYTOSKELETON CHANGES RELATED TO THE FORMATION OF NEUROFIBRILLARY TANGLES AND NEUROPIL THREADS

Frontal sections of the temporal lobe including the transentorhinal/en torhinal region, amygdala, and/or hippocampus from human adult brains are studied for cytoskeleton changes using immunostaining with the ant ibodies AT8 and Alz-50 and selective silver impregnation methods for n eurofibrillary changes of the Alzheimer type. For the purpose of corre lation, the two methods are carried out one after the other on the sam e section. Layer pre-alpha in the transentorhinal/entorhinal region ha rbours nerve cells which are among the first nerve cells in the entire brain to show the development of neurofibrillary changes. This presen ts the opportunity for study of both early events in the destruction o f the cytoskeleton in individual neurons, and to relate changes which occur in the neuronal processes in the absence of alterations in their immediate surroundings to those happening in the soma. Immunoreaction s with the AT8 antibody in particular reveal a clear sequence of chang es in the neuronal cytoskeleton. Group 1 neurons present initial cytos keleton changes in that the soma, dendrites, and axon are completely m arked by granular AT8 immunoreactive material. These neurons appear qu ite normal and turn out to be devoid of argyrophilic material when obs erved in silver-stained sections. Group 2 neurons show changes in the cellular processes. The terminal tuft of the apical dendrite is replac ed by tortuous varicose fibres and coarse granules. The distal protion s of the dendrites are curved and show appendages and thickened portio ns. Intensely homogeneously immunostained rod-like inclusions are enco untered in these thickened portions and in the soma. A number of these rod-like inclusions are visible after silver staining, as well. Group 3 neurons display even more pronounced alterations of their distal - most dendritic portions. The intermediate dendritic parts lose immunor eactivity, but the soma is homogeneously immunostained. Silver stainin g reveals in most of the distal dendritic parts neuropil threads, and in the soma a classic neurofibrillary tangle. Group 4 structures are m arked by accumulations of coarse AT8-immunoreactive granules. Silver s taining provides evidence that the fibrillary material has become an e xtraneuronal, ''early'' ghost tangle. Finally, group 5 structures pres ent ''late'' ghost tangles in silver-stained sections but fail to demo nstrate AT8 immunoreactivity. It is suggested that the altered tau pro tein shown by the antibody AT8 represents an early cytoskeleton change which eventually leads to the formation of argyrophilic neurofibrilla ry tangles and neuropil threads.