Chemists Reveal How Tau Proteins Form Alzheimer’s Disease Brain Tangles

The tangles found in the brains of those with Alzheimer's Disease are caused by the almost random mixing of two kinds of tau proteins.

Neurofibrillary tangles in the brain are one of the characteristics of Alzheimer's disease. These tau protein-based tangles prevent neurons from functioning correctly and have the potential to kill the cells.

In a recent study, MIT scientists described how the interaction of two varieties of tau proteins, called 3R and 4R tau, results in the formation of these tangles. The tangles may almost randomly recruit any tau protein in the brain, the researchers discovered. According to the experts, this characteristic may be a factor in the prevalence of Alzheimer's disease.

"The filament may recruit whichever tau version present in the environment to put onto the expanding filament, regardless of whether the end of an existing filament is a 3R or 4R tau protein. The ability of the tau structure in Alzheimer's disease to haphazardly incorporate any protein type is highly favorable, according to Mei Hong, an MIT professor of chemistry.

The study's senior author, Hong, just had it published in the magazine Nature Communications. The paper's primary authors are postdoc Pu Duan and graduate student Aurelio Dregni from MIT.

Tau serves as a stabilizer of microtubules in neurons in a healthy brain. Each of the three or four "repeats" that make up a tau protein has 31 amino acid residues. Various disorders can be caused by aberrant forms of 3R or 4R tau proteins.

Repeated head trauma leads to chronic traumatic encephalopathy, which is associated with aberrant 3R and 4R tau protein buildup, which is analogous to Alzheimer's disease. However, the majority of other tau-related neurodegenerative illnesses only include aberrant forms of either the 3R or 4R proteins, not both.

As a result of chemical alterations to the proteins that prevent them from performing their normal function, tau proteins start to tangle in Alzheimer's disease. It was unknown exactly how the 3R and 4R tau proteins interact at the molecular level to produce the lengthy filaments that make up each tangle.

One theory put up by Hong and her coworkers was that the filaments may be constructed from alternating blocks of several 3R and numerous 4R tau proteins. They also proposed that specific 3R and 4R tau molecules may switch places.

Nuclear magnetic resonance (NMR) spectroscopy was used by the researchers to investigate these possibilities. The researchers were able to determine the odds that each 3R tau protein is followed by a 4R tau and that each 4R tau is followed by a 3R tau protein in a filament by labeling 3R and 4R tau proteins with carbon and nitrogen isotopes that can be detected using NMR.

The researchers started with aberrant tau proteins extracted from post-mortem brain samples of Alzheimer's patients in order to make their filaments. These "seeds" were then introduced to a solution that contained an equal amount of regular 3R and 4R tau proteins. The seeds attracted the normal tau proteins to create long filaments.

Unexpectedly, the NMR examination of these seeded filaments revealed that the assembly of these 3R and 4R tau proteins was essentially random. A 3R tau was slightly more than 50% likely to be followed by a 4R tau, whereas a 4R tau was around 40% likely to be followed by a 3R tau. Even while the pool of accessible tau proteins was evenly split between 3R and 4R, the majority of the tau filament in Alzheimer's disease was composed of 4R proteins, accounting for 60% of the filament. 3R and 4R tau proteins are also present in nearly similar levels in the human brain.

Comparatively to illnesses that exclusively include 4R or 3R tau proteins, this form of assembly, or "fluent molecular mixing," may be a factor in the incidence of Alzheimer's disease, according to Hong.

According to "our understanding," this would encourage the proliferation and development of the toxic tau conformation associated with Alzheimer's disease.

The researchers demonstrated that the tau filaments they produced in the lab have a structure that is strikingly similar to that seen in people with Alzheimer's disease, but they do not resemble filaments grown exclusively from normal tau proteins, as suggested by colleagues at the University of Pennsylvania School of Medicine led by Professor Virginia Lee.

The tau filaments they produced formed clumps in the dendrites and axons of mouse neurons cultured in a lab dish, mimicking the deadly consequences of Alzheimer's tangles.

The researchers now intend to further investigate the structure of the floppier protein segments that stretch out from this core. The present publication largely focused on the nature of the hard inner core of the filaments. The cause of this protein's transition from a normal, intrinsically disordered form to the toxic, misfolded, and beta-sheet-rich state found in Alzheimer's disease brains is something Hong and colleagues are trying to understand.

Fluent molecular mixing of Tau isoforms in Alzheimer's disease neurofibrillary tangles was described in Nature Communications on May 27, 2022, by Aurelio J. Dregni, Pu Duan, Hong Xu, Lakshmi Changolkar, Nadia El Mammeri, Virginia M.-Y. Lee, and Mei Hong.

MASSACHUSETTS INSTITUTE OF TECHNOLOGY