Image reconstruction of the Alzheimer paired helical filament

The paired helical filament (PHF) is the principal constituent of the neurofibrillary tangles that occur in the brain in senile dementias of the Alzheimer type. We have previously shown from fragmentation patterns of isolated PHFs that they consist of a regularly repeating subunit, which is axially compact and not an extended fibrous molecule or protofilament. Here we present diffraction patterns of PHFs and an objective reconstruction of the cross-sectional density of the PHF computed from the diffraction patterns. We demonstrate the presence of an axial periodicity (3 nm) in PHFs. These results establish conclusively that the PHF is made up of a double helical stack of transversely oriented subunits, each of which has three domains, and precludes purely descriptive models based on helical rearrangements of preformed cytoskeletal polymers or protofilaments. The structure is of the type that might arise by the de novo assembly of a single structural subunit, which appears to be produced in considerable abundance in those neurons where tangles form.