Alzheimer’s tau structure revealed in first-of-its-kind study

Written by Lauren Pulling, Editor

Researchers at the Medical Research Council Laboratory of Molecular Biology (MRC LMB; Cambridge, UK), have presented the atomic structures of the abnormal tau filaments that are associated with Alzheimer’s disease (AD). In the first study of its kind, findings show cryo-electron microscopy maps and associated atomic models of paired helical and straight filaments taken from the brain of a patient with AD.
The authors of the study – published this week in Nature – suggest that these findings could also demonstrate how tau protein may form different filaments in other neurodegenerative diseases.

Tau was first identified as an integral component of AD lesions almost 30 years ago; however, this new study is the first to identify the atomic structure of the protein filaments. Tau filaments were taken from the brain of a patient who had died with AD. These were then imaged with cryo-electron microscopy and new software was used to calculate the corresponding atomic structures.

Sjors Scheres (MRC LMB), co-senior author, said: “It’s very exciting that we were able to use this new technique to visualise filaments from a diseased brain as previous work depended on artificial samples assembled in the laboratory.  Amyloid structures can form in many different ways, so it has been unclear how close these lab versions resembled those in human disease.

“Knowing which parts of tau are important for filament formation is relevant for the development of drugs. For example, many pharmaceutical companies are currently using different parts of tau in tests to measure the effect of different drugs on filament formation; this new knowledge should significantly increase the accuracy of such tests.”

Co-senior author Michel Goedert (MRC LMB) added: “We have known for almost three decades that the abnormal assembly of tau protein into filaments is a defining characteristic of AD. In 1998, the dysfunction of tau protein was shown to be sufficient for neurodegeneration and dementia. In 2009, the prion-like properties of assembled tau were identified. These properties allow the abnormal form to convert previously normal forms.

“Until now the high-resolution structures of tau or any other disease-causing filaments from human brain tissue have remained unknown. This new work will help to develop better compounds for diagnosing and treating Alzheimer’s and other diseases which involve defective tau.”

Sources: Fitzpatrick AWP, Falcon B, He S et al. Cryo-EM structures of tau filaments from Alzheimer’s disease. Nature doi:10.1038/nature23002 (2017) (Epub ahead of print);