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Atomic Structure of Key Alzheimer's Protein Uncovered By Scientists

Recently, scientists have captured high-resolution images of the abnormal tau protein for the first time ever. These proteins are one of the key markets of Alzheimer’s and these images are the first to reveal their chemical structure.

With these images, scientists now have an unprecedented glimpse into how these harmful protein deposits work at a deeper molecular level. 

They could also lead to numerous treatment options, with the goal of preventing them from forming. Giving doctors a new way to combat Alzheimer’s and dementia.  

"This is a tremendous step forward," explains one of the researchers, Bernardino Ghetti from Indiana University.

"It's clear that tau is extremely important to the progression of Alzheimer's disease and certain forms of dementia. 

In terms of designing therapeutic agents, the possibilities are now enormous”, he went on to say. 

In the new study, researchers led by a team from MRC Laboratory of Molecular Biology (LMB) in the UK used a deceased patient with a confirmed diagnosis of Alzheimer’s. 

Next, they extracted tau protein filaments from the subject’s brain and imaged them using a technique called cryo-electron microscopy (cryo-EM).
 

Tau protein filaments. Credit: Scheres Group MRC-LMB

There are two kinds of proteins associated with Alzheimer’s disease. Tau filaments, which form inside the nerve cell and amyloid beta proteins, which form outside the cells. 

Tau proteins act as a stabilizer in healthy brains, but when proteins become defective they begin to form bundles of filaments that become tangled.

These dysfunctional filaments are thought to impede communication between brain cells, which leads to loss of cognitive function and the neurodegeneration seen in Alzheimer’s disease.

For decades, researchers have known about the involvement of tau proteins in Alzheimer’s disease, but it wasn’t until recently that they’ve actually been able to see them up close. 

And with the insights gained through the cryo-EM imaging more opportunities for drug discovery targeting tau are possible.

"Drugs that could clear away clumps of protein in the brain are a key goal for researchers, but to directly affect these proteins, molecules that make up a drug need to latch on and bind to their surface," explains Rosa Sancho, the head of research at Alzheimer's Research UK. 

"Knowing the precise shape of these complex protein structures is enormously valuable in guiding the development of targeted drugs."

And while there is an abundance of research available examining how abnormal tau and amyloid beta proteins function, researchers weren’t sure of the differences between artificial samples created in the lab and those that form in the lab.

But now, with the insights gained from the tau structures generated from the deceased patient, researchers can now investigate how the abnormal filaments actually function at the atomic level in the human brain.

The good news is that according to the research team, studying these tangles won’t just benefit Alzheimer's research.

As neuroscientist Michel Goedert from LMB told James Gallagher told BBC News. "This is a big step forward as far as tau goes but it is bigger than that”.

"This is the first time anybody has determined the high-resolution structure [from human brain samples] for any of these diseases. The next step is to use this information to study the mechanisms of neurodegeneration”, he continued. 

The full ramifications of this new discovery won’t be known, until scientists have the opportunity to expand and follow up on their discovery. But one thing is clear, it could be a turning point in the ability to counter these brain damaging proteins. 

So much so that Ghetti describes the results as one of the major discoveries of the last quarter century of Alzheimer's research.

With that being said, it may take several more years (or even decades) for new treatments to come from this discovery – but at least it takes us one step closer to that goal, which before now appeared to be impossible. 

"It's like shooting in the dark – you can still hit something but you are much more likely to hit if you know what the structure is," one of the team members, LMB's Sjors Scheres explained. 

"We are excited – it opens up a whole new era in this field, it really does."

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References:

1. "IU Researchers Help Provide First Look At Atomic Structures Of Protein Tangles Found In Alzheimer's Disease : Newscenter : School Of Medicine." News.medicine.iu.edu. N.p., 2017.

2. Fitzpatrick, Anthony W. P. et al. "Cryo-EM Structures Of Tau Filaments From Alzheimer’S Disease." Nature 547.7662 (2017): 185-190.

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