TWISTED RIBBON STRUCTURE OF PAIRED HELICAL FILAMENTS REVEALED BY ATOMIC-FORCE MICROSCOPY

Progressive deposition of phosphorylated tau into the paired helical f ilaments (PHF) that compose neurofibrillary tangles, dystrophic neurit es, and neuropil threads is an obligate feature of Alzheimer's disease . Tbe standard model of PHF structure, derived from electron microscop ic studies, suggests that two 8- to 10-nm filaments each composed of t hree to four protofilaments are wound into a helix with a maximal diam eter of similar to 20 nm and a half period of 65 to 80 nm. However, re cent vertical platinium-carbon replicas of PHF more closely resemble a thin helical ribbon without constitutive protofilaments. Here we repo rt that native PHF imaged with an atomic force microscope appear as tw isted ribbons rather than the generally accepted structure derived fro m electron microscopic studies. These data imply that the assembly of PHF is not due to the twisting of pair-wise filaments but rather the h elical winding of self-associated tau molecules arranged into a flatte ned structure. Future structural models of PHF should be based on quan titative data obtained from imaging techniques, such as scanning probe microscopy, which do not require harsh specimen preparation procedure s.