Cryo-EM solves structure of Alzheimer's protein
Image: Tau filament rendered in white and blue. [Thomas Martin]
In a world first, UK-based researchers have used cryo-electron microscopy to determine the structure of tau filaments - aggregates of the Alzheimer's protein.
Studying the brain of a 74-year-old woman that had died from the disease, Professor Sjors Scheres from MRC Laboratory of Molecular Biology, Cambridge, and colleagues, provide a detailed description of the distinct helical and straight filaments, helping to explain why these filaments form aggregates in the brain.
“Tau protein, one of the hallmarks of Alzheimer’s disease, has never been seen in this level of detail before," highlights Dr James Pickett, Head of Research at the Alzheimer’s Society.
"Many drugs work like a key in a lock, and this discovery shows us the inner workings of the tau protein ‘lock’, he adds. "The ability to picture what the lock looks like could help scientists design more precise drugs that act on the tau protein and stop damage to the brain."
To determine the structure of the Tau filaments, the researchers plunged purified tissue samples taken from the woman's cerebral cortex, into liquid ethane using an FEI Vitrobot Mark IV.
Thousands of Cryo-EM images of the filaments were then acquired on a Gatan K2-Summit detector in super-resolution counting mode on an FEI Titan Krios at 300 kV.
The researchers used computer software - RELION 2.0 - to reconstruct the structure of the filaments to 3.4–3.5 Å resolution, discovering that the filament cores are made of two identical protofilaments comprising residues of the tau protein.
These adopt a combined cross-β/β-helix structure and define the seed for tau aggregation.
"Our results demonstrate that amyloid structures from human brain may be obtained by cryo-electron microscopy," points out Scheres. "This opens up new possibilities for studying the molecular mechanisms underlying a wide range of neurodegenerative diseases."
Research is published in Nature.