. Paired helical filaments in electron microscopy of Alzheimer's disease. Nature. 1963 Jan;197:192-3.

Abstract:

In the light microscope, the characteristic change in the neurones of the cerebral cortex in Alzheimer's disease is the presence of dense bundles of argyrophilic fibrils. They are coiled into skeins or 'squash racket' shapes, and appear to fill most of the perikaryal cytoplasm, sometimes giving the cell a swollen appearance. It has been suggested by Divry that the fibrils are extra-cellular except in the later stages of the change. The fibrils stain with Congo red, and this results in a type of birefringence suggesting the presence of longitudinally arranged micelles in the fibrillar bundles. These well-known findings would lead one to expect the presence of fine filaments associated with these cells in the electron microscope, and if intracellular, these might be neurofilaments, which are suggested by Gray and Guillery to be the basis of neurofibrillary argyrophilia.

This is a preliminary report of observations in the electron microscope on cortical biopsies from three cases of Alzheimer's disease, confirmed by light microscopy. In each case the biopsy was taken from the parietal lobe through a burr hole prior to ventriculography. The specimen was cooled rapidly below 2O degrees C after removal and cut into small pieces in the fixative within 5 mm of removal. The fixatives were 1 per cent OsO4 or O.6 per cent KMnO4 buffered to PH 7.2, and fixation was continued for 4 h. The tissue was then dehydrated in alcohol and embedded in 'Araldite'. Most of the observations were made on material which had been stained in I per cent alcoholic phosphotungstic acid before embedding. Most of the neurones seen were normal, being similar to those seen in biopsies from normal animals and from human cortex exposed for removal of tumours. A number of neurones, however, were very different from normal.

They contained thick bundles of parallel filaments of indefinite length, sweeping around the nucleus, often leaving only a thin rim of normal cytoplasm near the cell membrane. In places the filaments diverged or formed whorls, and some planes of section gave the impression of a ring. They could be found in cell processes in the neuropil. In the later stages of the change the cytoplasm outside the bundles still appeared normal in fine structure, but compressed against the cell membrane, so that the ribosomes appeared as a dense mass. In the middle of the bundles however, some lamellated bodies were found, similar to those described by Webster as degenerating mitochondria. Other bodies were found in the bundles consisting of vesicles 500-1000 A in diameter embedded in a dense granular mass of irregular shape about 1 micron in diameter.

At high magnifications the filaments composing the bundles were seen to be double helices. These consisted of two 100 A filaments 150 A from centre to centre, and completing one full turn in 1600 A. Their appearance varied with the thickness and obliquity of the section. When parallel to the plane of section they appeared as helices, though this single appearance could be interpreted as a regular series of fusiform swellings, or at high packing densities, as tubules, as described by Terry. In thick oblique sections they appeared as asymmetrical shapes, rough on one side and smooth on the other. Thin oblique or transverse sections did not show dots or circles, as would be shown by single filaments, tubes or fusiform swellings, but dots paired with short curved segments, or two curved segments, or, very occasionally, a pair of dots. All these forms could be explained by a uniform helix with the dimensions described.

It is difficult to speculate on the nature of these structures. It is possible that they are neurofilaments occurring in vastly increased numbers and associated in pairs; though the individual filaments of each pair seem to be of higher density than neurofilaments, especially in unstained preparations. The tendency of these pathological filaments to stain with Congo red suggests a similarity to amyloid, but the later is known to be extra-cellular, and these filaments are intracellular.

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