Genesis of Toxic Tau in Alzheimer's Disease Revealed

Megan Brooks

July 16, 2018

New research provides novel insight into the shape-shifting nature of tau proteins, in findings that may aid in the development of therapies to stabilize the protein before it has the ability to aggregate and contribute to Alzheimer's disease (AD).

Researchers from UT Southwestern's O'Donnell Brain Institute in Dallas, Texas, found that tau proteins can convert from an inert form to a misfolded form that seeds the growth of toxic aggregates that contribute to the pathology of AD.

"We think of this as the Big Bang of tau pathology. This is a way of peering to the very beginning of the disease process," lead investigator Marc Diamond, PhD, director of UT Southwestern's Center for Alzheimer's and Neurodegenerative Diseases, said in a statement.

The results, published online July 10 in eLife, contradict the belief that tau is an intrinsically disordered protein with no distinct form, the researchers note.    

"Although tau monomer has been considered to be natively unstructured, our findings belie this assumption and suggest that initiation of pathological aggregation could begin with conversion of tau monomer from an inert to a seed-competent form," the investigators write.

Immediate Implications

The researchers purified and characterized the two distinct forms of tau from recombinant sources and human AD brain. They observed that the inert form is nontoxic, is stable for long periods, and does not easily aggregate. 

The seed-competent form helps convert inert tau into misfolded tau that forms toxic aggregates by seeding or self-assembly. Tau can slowly change from the inert to the seed-competent form.

"The identification of distinct and stable forms of tau monomer, including some that are uniquely seed-competent, bears directly on how we understand the initiation of protein aggregation in tauopathies," the researchers note.

"Personally, I think that this is the biggest thing that we have done because it offers fundamental and important insight into tau that has immediate implications for therapy and diagnosis," Diamond told Medscape Medical News.

If it's possible to detect seed-competent tau in healthy people, "we could anticipate disease, and that's been a major goal of our center — to develop diagnostic tests that could be applied to a healthy population, analogous to the way we use hemoglobin A1c to detect early diabetes," said Diamond.

In terms of therapeutics, "it may be possible to develop therapies to target only the bad forms of tau that are building up as opposed to all tau.  If the protein has two different defined structures, then you can envision making small molecules that stick to the normal or good form of tau and stabilize it before it converts to the bad form," he added.

"It is known that small molecules can bind to the inert conformation of proteins that are prone to misfolding, and thus prevent the conformational change that leads to amyloid diseases," Jeffery Kelly, PhD, from The Scripps Research Institute, La Jolla, California, notes in an accompanying editorial published with the study.  

"For example, transthyretin is another protein with two ways of folding, and whose toxic conformation damages various nervous systems, as well as the heart. However, drugs known as kinetic stabilizers can slow down the degenerative process by increasing the population of the properly folded conformation," Kelly explains.

He notes that three placebo-controlled clinical trials have shown that small molecules, such as the drugs tafamidis and diflunisal, can bind to the nonpathogenic form of transthyretin and stabilize it, "which prevents the protein from converting into the conformation that initiates aggregates and leads to degenerative pathologies," Kelly writes.

"This suggests that it should be possible to fashion similar kinetic stabilizers for the tau protein and offer better treatment for diseases such as Alzheimer's."

This research was funded by the National Institutes of Health, Rainwater Charitable Foundation, and Effie Marie Cain Endowed Scholarship. Diamond and Kelly have disclosed no relevant financial relationships.

eLife. Published online July 10, 2018. Full text, Editorial

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