Assembled tau filaments differ from native paired helical filaments as determined by scanning transmission electron microscopy (STEM)

Paired helical filaments (PHF) are abnormal, approximately 20-25-nm wide pe riodically twisted filaments, which accumulate in Alzheimer's disease (PLD) brain and other neurodegenerative disorders, including corticobasal degene ration (CBD). PHF are primarily composed of highly phosphorylated tau prote in. However, both phosphorylated and non-phosphorylated forms of tau are ab le to assemble in vitro into filaments similar in the ultrastructural appea rance to PI-IF. In the present study, filaments were assembled in vitro fro m unmodified recombinant human tau and the physical mass per unit length of filaments and the mass density were determined using scanning transmission electron microscopy (STEM). Two general types of filaments were observed. One type was composed of 11.4 nm-wide, 10-75 nm long, frequently twisted an d PHF-like filaments, with a mass per unit length (44 kDa/nm) approximately one third of that observed in isolated AD filaments. The other were straig ht filaments, approximately 6.8-nm wide and 0.2-2 mu m long, which often fo rmed parallel clusters of two or more filaments. Triple clusters were 19.2- nm wide and had a mass per unit length (70 kDa/nm) approximately two thirds of that seen in isolated AD filaments. Despite different morphology, both twisted and straight filaments had mass densities between 0.48-0.55 kDa/nm( 3). These values are significantly higher than those reported for PHF found either in AD (0.40 kDa/nm(3)) or CBD (0.33 kDa/nm(3)). These results sugge st that the packing of tau differs in vivo from that observed in vitro and that specific tau isoform content, elongation of tau molecules by phosphory lation or other factors may be required to reproduce pathological assembly. Therefore mass density determinations appear to be an important criterion in comparing various filaments. (C) 1998 Elsevier Science B.V. All rights r eserved.