Deformation of isolated neurofilaments and the pathogenesis of neurofibrillary pathology

Experimental structural alterations were studied in neurofilaments isolated from rat peripheral nerve. Structural alterations were induced in vitro by prolonged incubations of neurofilament-rich fractions in 0.1 M KCl prior to fixation and examination of neurofilaments by negative staining techniques. Neurofilaments appeared to retain their structural integrity during the first week of incubation. Subsequently, a progressive reduction in the numbers of intact neurofilaments coincided with the increasing appearance of neurofilamentous breakdown products. During the period of neurofilament breakdown, an increasing number of altered neurofilaments were observed. These abnormal neurofilaments were characterized primarily by axial enlargements with diameters frequently occurring in the 150-200 A range but measuring up to 250 A. Enlarged neurofilaments also showed a greater irregularity of their lateral margins and less ridigity in their linear course. A striking feature of enlarged neurofilaments was their tendency to display twisting deformations along their longitudinal axes. Twists occurred most frequently along neurofilaments of greatest diameter. The largest abnormal neurofilaments reveal multiple periodic twists, sometimes occurring at 800-1000 A intervals. These enlarged and twisted neurofilaments resembled the abnormal filaments described in neurofibrillary tangles and plaques. The demonstration of neurofilament plasticity as well as the resemblance of neurofilaments deformed in vitro to the abnormal filamentous structures of neurofibrillary tangles and plaques has led to the suggestion that the latter structures may be derived from alterations of normally-formed neurofilaments. Furthermore, it is proposed that the enlarged and twisted filaments of neurofibrillary pathology may arise from alterations in the turnover of neurofilaments or, more specifically, from deficiencies in the degradative processes by which these organelles are broken down.