The tangles found in the brains of persons with Alzheimer's Disease are caused by a practically 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.
“Whether the end of an existing filament is a 3R or 4R tau protein, the filament can recruit whichever tau version is in the environment to add onto the growing filament. It is very advantageous for the Alzheimer’s disease tau structure to have that property of randomly incorporating either version of the protein,” explains Mei Hong, a chemistry professor at MIT.
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.
Molecular mixing
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 influenced by abnormal 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. Despite the fact that the pool of accessible tau proteins was equally split between 3R and 4R, 4R proteins made up 60% of the tau filament in Alzheimer's disease. 3R and 4R tau proteins are also present in nearly similar levels in the human brain.
Compared to illnesses that solely include 4R or 3R tau proteins, Hong believes this form of assembly, which the researchers refer to as "fluent molecular mixing," may help explain the incidence of Alzheimer's disease.
“Our interpretation is that this would favor the spread and the growth of the toxic Alzheimer’s disease tau conformation,” she states.
Toxic effects
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.
In the dendrites and axons of mouse neurons cultured in a lab dish, the tau filaments they produced also mimicked the harmful consequences of Alzheimer's tangles by forming aggregates.
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.
“We would like to figure out just how this protein goes from a healthy and intrinsically disordered state to this toxic, misfolded, and beta-sheet rich state in Alzheimer’s disease brains,” Hong explains.
Reference: “Fluent molecular mixing of Tau isoforms in Alzheimer’s disease neurofibrillary tangles” by Aurelio J. Dregni, Pu Duan, Hong Xu, Lakshmi Changolkar, Nadia El Mammeri, Virginia M.-Y. Lee and Mei Hong, 27 May 2022, Nature Communications.
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