We synthesized oligopeptides corresponding to the sequences reported for the amyloid core and neurofibrillary tangle proteins found in brains of Alzheimer's patients. Antibody was raised against these peptides. Using these immune reagents, we demonstrated that there are proteins in normal controls which cross-react with the antisera and are probably the precursors of the pathologically accumulated protein. We explored the possibility that the amyloid and neurofibrillary tangles are derived from neurofilaments, the intermediate filament of neurons. We isolated cDNA and genomic clones of the small and mid-size neurofilament subunit of humans. These cDNA clones were sequenced to determine the amino acid sequence of the protein. The genomic clones were sequenced to define the organization of the gene and the position of the introns. The predicted protein for the mid-size neurofilament demonstrates a highly charged, highly Alpha-helical tail region with a proline and serine-rich 13 amino acid sequence repeated tandemly six times. The repeat regions appear to allow the otherwise helical protein to bend, indicating that phosphorylation at this site might alter the protein's conformation. The gene structure of the mid-size subunit and small subunit are similar to one another, but different from the general structure found for the other intermediate filaments of the cell. These results support the notion that both subunits of neurofilaments had a common origin. A comparison of the amino acid sequences of the small and mid-size neurofilaments with those found for neurofibrillary tangles and the amyloid protein reveals no homology, indicating that the latter were not derived from the former by an degradative procedure.
