One of the hallmarks of Alzheimer’s disease is the presence of neurofibrillary tangles in the brain. These nodes, made of tau proteins, hinder the normal functioning of neurons and can cause the cells to die.
A new study from MIT chemists has revealed how two types of tau proteins, known as 3R and 4R tau, mix together to form these knots. The researchers found that the tangles can recruit any tau protein in the brain in an almost random way. This feature may contribute to the prevalence of Alzheimer’s disease, the researchers say.
“Whether the end of an existing filament is a 3R or 4R tau protein, the filament can recruit any version of tau in the environment to add to the growing filament. It is very beneficial to the tau structure of the Alzheimer’s disease to have the ability to randomly include both versions of the protein,” said Mei Hong, an MIT professor of chemistry.
Hong is the lead author of the study, which appears today in Nature Communications. MIT graduate student Aurelio Dregni and postdoc Pu Duan are the lead authors of the paper.
In the healthy brain, tau acts as a stabilizer of microtubules in neurons. Each tau protein consists of three or four “repeats”, each consisting of 31 amino acid residues. Abnormal versions of 3R or 4R tau proteins can contribute to a variety of diseases.
Chronic traumatic encephalopathy, caused by repetitive head trauma, has been linked to abnormal accumulation of both 3R and 4R tau proteins, similar to Alzheimer’s disease. However, most other neurodegenerative diseases involving tau have abnormal versions of 3R or 4R proteins, but not both.
In Alzheimer’s disease, tau proteins begin to form tangles in response to chemical modifications of the proteins that disrupt their normal function. Each tangle consists of long filaments of 3R and 4R tau proteins, but it was not known exactly how the proteins combine at the molecular level to generate these long filaments.
One possibility Hong and her colleagues considered was that the filaments could be made of alternating blocks of many 3R-tau proteins or many 4R-tau proteins. Or, they hypothesized, individual molecules of 3R and 4R tau could alternate.
The researchers set out to explore these possibilities using nuclear magnetic resonance (NMR) spectroscopy. By labeling 3R and 4R tau proteins with carbon and nitrogen isotopes that can be detected by NMR, the researchers were able to calculate the probabilities that each 3R tau protein is followed by a 4R tau and that each 4R tau becomes followed by a 3R tau protein in a filament.
To produce their filaments, the researchers started with abnormal tau proteins from postmortem brain samples from Alzheimer’s patients. These “seeds” were added to a solution containing equal concentrations of normal 3R and 4R tau proteins, which were recruited by the seeds to form long filaments.
To the researchers’ surprise, their NMR analysis showed that the assembly of these 3R and 4R tau proteins in these seeded filaments was almost random. A 4R tau was about 40 percent likely followed by a 3R tau, while a 3R tau was likely followed by a 4R tau just over 50 percent. Overall, 4R proteins made up 60 percent of the tau filament for Alzheimer’s disease, although the pool of available tau proteins was evenly split between 3R and 4R. In the human brain, 3R and 4R tau proteins are also found in approximately equal amounts.
This type of assembly, which the researchers call “fluid molecular mixing,” may contribute to the prevalence of Alzheimer’s disease, compared to diseases involving only 4R or 3R tau proteins, Hong says.
“Our interpretation is that this would promote the spread and growth of the toxic tau conformation of Alzheimer’s disease,” she says.
Working with collaborators at the University of Pennsylvania School of Medicine, led by Professor Virginia Lee, the researchers showed that the tau filaments they generated in the lab have a structure very similar to that found in human patients with the disease. Alzheimer’s disease, but they do not resemble filaments grown solely from normal tau proteins.
The tau filaments they produced also replicated the toxic effects of Alzheimer’s disease tangles, forming aggregates in the dendrites and axons of mouse neurons grown in a lab dish.
The current paper mainly focused on the structure of the stiff inner core of the filaments, but the researchers now hope to further study the structure of the slacker protein segments extending from this core. “We’d like to find out how this protein goes from a healthy and intrinsically disordered state to this toxic, misfolded, and beta-leaf-rich state in the Alzheimer’s brain,” says Hong.
The research was funded by the National Institutes of Health and the BrightFocus Foundation.