X-ray diffraction from intraneuronal paired helical filaments and extraneuronal amyloid fibers in Alzheimer disease indicates cross-beta conformation.
Information about the structure of the paired helical filaments (PHF) that accumulate within human neurons and the amyloid fibers that accumulate in the extracellular spaces between neurons in Alzheimer disease has so far depended on electron microscopy of thin-sectioned or negatively stained material. To determine the protein conformation of these abnormal fibers, we have obtained x-ray diffraction patterns from unfixed human brain fractions highly enriched in PHF and from purified amyloid cores isolated from senile plaques. The predominant x-ray scatter evident from both types of samples, either wet or dry, is a sharp reflection at 4.76-A spacing and a diffuse one at about 10.6-A spacing. These features are characteristic of a beta-pleated sheet type of protein conformation. In doubly oriented dried pellets of PHF fractions, the two reflections are accentuated at right angles to each other and the arc at 4.76-A spacing is in the fiber direction indicating a cross-beta conformation. From the integral widths of the reflections we estimate the cross-beta crystallite to be about 80 A long in the fiber direction and about 40 A thick. These dimensions correspond to approximately four pleated sheets, each of which consists of approximately 16 hydrogen-bonded polypeptide chains running normal to the fiber direction. The cross-beta conformation of PHF and amyloid fibers that we have found from x-ray diffraction is in contrast to the predominant alpha-helical coiled-coil conformation of the neurofilaments with which they share epitopes and from which they have been postulated to derive.
Kirschner
D A
DA
Abraham
C
C
Selkoe
D J
DJ
D000544:Alzheimer Disease / Q000473:pathology*; D000682:Amyloid; D003599:Cytoskeleton / Q000648:ultrastructure*; D006801:Humans; D007382:Intermediate Filaments / Q000648:ultrastructure*; D046911:Macromolecular Substances; D011487:Protein Conformation; D014961:X-Ray Diffraction
D000682:Amyloid; D046911:Macromolecular Substances