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First-ever atomic look at tau fibril structure in Alzheimer's reveals detailed pathways

An international team of scientists has made a major step forward in Alzheimer’s research: breaking the atomic imaging barrier for tau filaments, which make up the disease’s signature tangles.

Researchers used cryo-electron microscopy (cryo-EM) of tau filaments extracted from the brain of a 74-year old woman who had been diagnosed with Alzheimer’s 10 years before her death. Cryo-EM allows electron microscopy imaging of hydrated specimens frozen at cryogenic temperatures, helping scientists to view delicate cellular structures and proteins at extremely high resolution without the need for fixatives or dyes.

The images produced gave the global Alzheimer’s research community a groundbreaking look at the structure of tau fibrils – “the tangles untangled” as one of the researchers described it – and demonstrated that amyloid structures from human brain could be characterized at a most basic level. The approach opens up new possibilities for both studying the molecular mechanisms underlying a wide range of neurodegenerative diseases and for prevention, diagnosis and treatment.

Development of new software was crucial to the effort, enabling calculations to sharpen and refine images of tau filament structure with sufficient detail. The project was also trailblazing in using tau amyloid filaments that were taken from the brain of a person who was known to have the disease. Previous tau structures were assembled in the lab.

The atomic-level look at tau revealed stacks of concentric double “C” shapes, with a “capital C” shape surrounding a second, “lowercase” c shape reversing itself and curling tightly back inside the first curve. These stacks of multiple copies of amyloid tau filaments run parallel, like finely woven fabric.

The closer look at tau gives insight into why it has proven difficult for scientists to target with potential therapeutics: the tight configuration keeps out water molecules, creating what is known as a “steric zipper.” This formation makes the filaments more stable, which in turn makes it more difficult for the cells’ natural clearing functions to remove. Further, the researchers said, the configuration of the filament proved to be a surprisingly complex structure, in some ways similar to others found in biology that have evolved to provide a survival advantage. Tau’s structure also proved to be unconventional in other places, in that similar sequences didn’t fit predictable structure patterns scientists had expected.

The Alzheimer’s research community is eager for further work on this project in the future, with scientists looking to examine different types of tau. The research team noted that the improved knowledge of tau structure was a tremendous step forward in understanding its role in the progression of Alzheimer’s and some related dementias, with enormous potential for the exploration of possible new therapies.

The work received partial support from the National Institute on Aging at NIH (P30-AG010133), the Indiana Alzheimer Disease Center.

Reference: Fitzpatrick A., et al. Cryo-EM structures of tau filaments from Alzheimer’s disease. Nature. 2017 Jul 13;547(7662):185-190.