Many neurological disorders are characterized by the formation of abnormal aggregates in which proteins tend to adopt a β-sheet structure. This fact has led to the suspicion that β-sheet formation might be a general mechanism for the development of aggregates in conditions as diverse as Alzheimer's disease and transmissible spongiform encephalopathy. But new data from Sadqi et al., published in Biochemistry, indicate that there is at least one important exception. They report that paired helical filaments (PHFs) — the main intraneuronal aggregate in Alzheimer's disease — have an α-helical conformation.

The tau protein is the main constituent of PHFs. Previous data had shown that tau lacks any regular structure in solution, and earlier attempts to determine the structure of PHFs grown in vitro or isolated from the brain found a similar lack of structural order. Sadqi et al. isolated PHFs directly from the brains of people with Alzheimer's disease, and set out to determine their structure by using a combination of Fourier transform infrared spectroscopy and far-ultraviolet circular dichroism. They found that PHFs are comprised of α-helices that, judging by their resistance to protease digestion and thermal denaturation, seem to be quite stable. Moreover, the authors found evidence that the α-helical configuration of PHFs is homogeneous. By obtaining circular-dichroism spectra during thermal denaturation, they found that PHFs melt as a homogeneous structure, with no sign of β-sheets even at the core of the aggregate.

As the tau protein has no regular structure in solution, the data imply that the α-helical configuration of PHFs emerges largely from protein–protein interactions. How this structural change takes place remains to be elucidated. But more significantly, the data of Sadqi et al. indicate that α-helix formation might also be a mechanism for the development of protein aggregates. It will be important to determine how widespread such a mechanism might be in other neurological disorders.