ALTERATIONS IN NEUROFILAMENT PROTEIN IMMUNOREACTIVITY IN HUMAN HIPPOCAMPAL-NEURONS RELATED TO NORMAL AGING AND ALZHEIMERS-DISEASE

The distribution of immunoreactivity for the neurofilament triplet cla ss of intermediate filament proteins was examined in the hippocampus o f young, adult and elderly control cases and compared to that of Alzhe imer's disease cases. In a similar fashion to non-human mammalian spec ies, pyramidal neurons in the CA1 region showed a very low degree of n eurofilament triplet immunoreactivity in the three younger control cas es examined. However, in the other control cases of 49 years of age an d older, many CA1 pyramidal neurons showed elevated neurofilament immu noreactivity. In the Alzheimer's disease cases, most of the surviving CA1 neurons showed intense labeling for the neurofilament triplet prot eins, with many of these neurons giving off abnormal ''sprouting'' pro cesses. Double labeling demonstrated that many of these neurons contai ned tangle-like or granular material that was immunoreactive for abnor mal forms of tau and stained with thioflavine S, indicating that these neurons are in a transitional degenerative stage. An antibody to phos phorylated neurofilament proteins labeled a subset of neurofibrillary tangles in the Alzheimer's disease cases. However, following formic ac id pre-treatment, the number of neurofibrillary tangles showing phosph orylated neurofilament protein immunoreactivity increased, with double labeling confirming that all of the tau-immunoreactive neurofibrillar y tangles were also immunoreactive for phosphorylated neurofilament pr oteins. Immunoblotting demonstrated that there was a proportionately g reater amount of the neurofilament triplet subunit proteins in hippoca mpal tissue from Alzheimer's disease cases as compared to controls. Th ese results indicate that there are changes in the cytoskeleton of CA1 neurons associated with age which are likely to involve an increase i n the level of neurofilament proteins and may be a predisposing factor contributing towards their high degree of vulnerability in degenerati ve conditions such as Alzheimer's disease. The cellular factors affect ing hippocampal neurons during aging may be potentiated in Alzheimer's disease to result in even higher levels of intracellular neurofilamen t proteins and the progressive alterations of neurofilaments and other cytoskeletal proteins that finally results in neurofibrillary tangle formation and cellular degeneration.