Alzheimer’s Disease: MIT Study Shows How Tau Protein Tangles Form

A new study by researchers from the Massachusetts Institute of Technology (MIT) has shown how tau protein tangles, typical features of Alzheimer’s disease, form to weaken the ability of neurons to function efficiently.

Alzheimer's disease

Alzheimer’s disease

In the study published in Nature Communications, scientists discovered how two tau protein types – 3R and 4R tau – combine to form these tangles. They observed that these tangles are capable of enlisting any of the brain’s tau proteins in a somewhat random manner. This phenomenon may explain the incidence of Alzheimer’s disease to an extent, according to the researchers.

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“Whether the end of an existing filament is a 3R or 4R tau protein, the filament can recruit whichever tau protein is in the environment to add onto the growing filament,” explained senior study author Mei Hong, a professor of chemistry at MIT. “It is very advantageous for the Alzheimer’s disease tau structure to have that property of randomly incorporating either version of the protein.”

Tau proteins and disorders

Tau proteins help in maintaining the stability of microtubules in neurons in a healthy human brain. They are in abundance in brain cells.

These tau proteins are often classified based on whether they have three or four repeat domains or simply “repeats.” This is how 3R and 4R labels came about. Each of these repeats features 31 amino acid residues.

A range of disorders can result from aberrant variants of 3R or 4R tau proteins.

A buildup of anomalous tau proteins is at the core of Alzheimer’s disease. Abnormal chemical changes make tau proteins cut off from microtubules and attach to other tau molecules. This produces threads that in the long run come together to form tangles. Both 3R and 4R tau proteins are involved in this occurrence.

An accretion of abnormal 3R and 4R tau proteins is also seen in chronic traumatic encephalopathy (CTE), a progressive brain disorder resulting from repeated blows to the head. However, nearly all other neurodegenerative conditions relating to tau present abnormal 3R or 4R tau, not both.

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Until now, it was not exactly clear how 3R and 4R tau proteins merge at the molecular level to form the long filaments that make up each tangle.

Molecular mixing

Researchers in this study thought the long filaments probably resulted from alternating blocks of numerous 3R or 4R tau proteins. Another theory was that they possibly formed from individual 3R or 4R tau molecules that alternated.

To test its hypotheses, the research team obtained abnormal tau proteins from the brain samples of deceased Alzheimer’s patients. These irregular proteins were put into a solution with equal amounts of healthy 3R and 4R tau proteins. The team observed that the “seeds” (abnormal proteins) recruited the healthy tau proteins to create long filaments.

The researchers had labeled 3R and 4R tau with isotopes of carbon and nitrogen to enable detection with nuclear magnetic resonance (NMR) spectroscopy. They were surprised to find that the assembly of tau proteins in the seeded filaments was just about random.

The likelihood that a 3R tau would follow a 4R tau was roughly 40 percent, the researchers found. And the chances of a 4R tau coming after a 3R tau were a little over 50 percent. In spite of the pool having even concentrations of 3R and 4R tau proteins, similar to the human brain, the 4R variant accounted for 60 percent of the diseased filament.

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Hong said this assembly, which they dubbed “fluent molecular mixing,” may explain the rampancy of Alzheimer’s disease relative to other disorders that have to do with only 3R or 4R tau.

The filaments made by the MIT chemists were more comparable to those present in Alzheimer’s than those formed from healthy tau proteins. They exhibited similar toxicity as the tangles that typify the disorder as well.

References

Fluent molecular mixing of Tau isoforms in Alzheimer’s disease neurofibrillary tangles

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