New method identifies tau aggregates occurring in healthy body structures

Photo credit: Perelman School of Medicine at the University of Pennsylvania

It turns out that not all tau protein buildups are bad, and a team of researchers from the Perelman School of Medicine at the University of Pennsylvania came up with a method to show this. Using mammalian cell models, the researchers combined extremely high-resolution microscopy with machine learning to show that tau actually forms small aggregates when it is part of the body’s normal physiology. This would allow them to differentiate between those aggregates found in healthy conditions and those associated with neurological disease, potentially opening the door to screening for treatments that could break up harmful aggregates. This research was published in the Proceedings of the National Academy of Sciences.

“There aren’t many tools that can be used to visualize small aggregates of pathological protein in cells,” said the study’s lead author, Melike Lakadamyali, Ph.D., an associate professor of physiology. ‘However, we believe that through machine learning, informed by high-resolution microscopy, we were able to show that tau forms both normal physiological aggregates and various pathological aggregates. In this way, we have created a useful method that is the basis for new research Might make into the appropriate treatments for tau-related pathologies. “

Tau is a protein that binds to the microtubule structure of axons – which act like highways in nerve cells. Previously it was assumed that tau aggregates only form when tau falls from the microtubules. These have been linked to some neurological disorders, including Alzheimer’s and other types of dementia. However, it turns out that small tau aggregates can also form outside of disease states.

“Actually, it is valuable to know which tau aggregates are part of the nervous system of a healthy person and which have formed harmful aggregates,” said the lead author of the study, Melina Theoni Gyparaki, a doctoral student in Lakadamyali’s laboratory. “Unfortunately, there has not yet been a process that was sensitive enough to make this distinction within cells. So we set out to create one using mammalian cell models.”

Initially, the researchers used extremely high-resolution microscopes with which individual molecules can be examined in order to differentiate between physiological and pathological oligomers (molecular formations). Monomers, dimers, and trimers, which are oligomers composed of one, two, and three tau molecules, respectively, were most likely associated with healthy physiological states because they were associated with microtubules and regular function.

When the team examined tau structures associated with a mammalian cell model that approximates frontotemporal dementia with parkinsonism associated with chromosome 17 (FTDP-17) – a disease associated with tau aggregation – the structures were larger and more complex. These appeared to be the pathological tau aggregates that broke off.

With the differences in configuration found, the researchers developed a machine learning algorithm to classify the pathological tau aggregates based on their shape alone. In addition, they used antibodies that can recognize and differentiate when the tau aggregates become “hyperphosphorylated” – when they take up many phosphate groups and tend to break off detrimentally. The combination of these methods showed that tau, which contains phosphate groups on certain amino acids, in contrast to other forms of tau aggregates, forms rather linear fibrils, a thin structure.

“The method we developed to identify tau aggregates is not yet a diagnostic tool, but we believe it will be a useful research tool for anyone interested in studying the mechanisms that lead to pathological protein oligomerization in neurodegenerative diseases Illnesses cause, “said Lakadamyali.

Tau aggregates are not the only ones that can be used to classify this method. There is an opportunity to use it on other potentially pathological protein buildups like alpha-synuclein, which is associated with Parkinson’s disease, or huntingtin, which is associated with Huntington’s disease. It could also be used to look for possible treatments for these conditions that don’t harm the body’s regular protein complexes.

The team is currently investigating possible mechanisms for deleting tau aggregates and identifying what other pathways might be helpful in this regard.

“We are also using the method we developed to visualize aggregates of tau in human post-mortem brain tissue slices from Alzheimer’s disease to determine the role of tau post-translational modifications in aggregation,” said Lakadamyali.

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More information:
Melina Theoni Gyparaki et al., Tau Forms Oligomeric Complexes on Microtubules Different from Tau Aggregates, Proceedings of the National Academy of Sciences (2021). DOI: 10.1073 / pnas.2021461118 Provided by the Perelman School of Medicine at the University of Pennsylvania

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