Northwestern scientists studying proteins linked to Alzheimer’s found a single spot that helps harmful tau clumps spread; blocking that hotspot with a chemical tag stopped the clumps from growing in lab tests

Northwestern scientists found a hydrophobic tau protein hotspot where water molecules help trigger interactions that drive harmful clump formation.

Buried deep in the brain, a protein that normally helps sustain nerve cells can be a source of trouble. When tau proteins change from their normal shape, they can start to cling together, creating tangled structures linked to Alzheimer’s disease and other forms of dementia, an online report from Northwestern University says. Scientists have long grappled with the question of how these misshapen proteins can persuade healthy ones to do the same. Now, researchers at Northwestern University may have discovered a key vulnerability in that process, a single molecular hotspot that could offer a new target for future treatments.

Finding the trigger for tau clumping

The study was conducted by scientists at Northwestern University in collaboration with colleagues at the University of California, Santa Barbara, who investigated the misfolding of tau proteins and their assembly into long, threadlike structures called fibrils. The research, published in the Proceedings of the National Academy of Sciences, identified that there is a particular region of tau that seems to dominate in triggering the process.Normally, tau proteins are flexible and have no fixed structure. But if they misfold they can latch onto existing fibrils and adopt the same abnormal shape. As more proteins attach to the growing structure, the fibrils become longer and may help create neurofibrillary tangles within neurons. Such deposits are characteristic of several neurodegenerative diseases such as Alzheimer’s disease and frontotemporal dementia. They can interfere with communication between nerve cells and contribute to the damage that occurs with cognitive decline.

The surprising role of water

The researchers found that the hotspot is in a hydrophobic part of tau — one that doesn’t readily interact with water. But proteins are in a watery cellular environment, so these regions still need to be protected from their surroundings. The water molecules form a protective layer or cap around the hotspot, but it is a dynamic layer. Researchers found that these water structures help determine where two tau proteins come together.When hotspots come together, the water around them is released. The energy released by this process stabilizes the interaction, allowing the incoming tau protein to align with an existing fibril and assume its misfolded shape. The report found that tau proteins stack in a uniform order to allow for continued growth of the fibrils. The newly identified hotspot appears to help coordinate that process, offering a molecular explanation for how an initially disordered protein can build an orderly, expanding structure.

When the hotspot is blocked, growth stops

To determine whether the hotspot was important, the team attached a chemical tag to the region they had found. In laboratory experiments, this intervention blocked the growth of tau fibrils. The researchers also identified two other areas, away from the hotspot. These interventions did not stop fibril growth, adding weight to the idea that the site identified plays a particularly important role in the process.Thus, disrupting this interaction could eventually be a way to stop misfolded tau from dragging other proteins along. But the experiments were conducted in the lab, and more research will be needed to determine if the approach can be safely and effectively used in living organisms.

A shortcut for future therapies perhaps

If a specific molecular target can be identified, researchers can hone in on potential treatments, rather than trying to block tau aggregation across the entire protein. The discovery could also lead to the development of diagnostic tools and synthetic tau fibrils that more accurately mimic disease-related structures for laboratory research.Scientists have struggled to create dependable models of these rogue proteins, making it difficult for them to study how various tau-related diseases progress and to test possible treatments.The Northwestern-led study shows how a specific region helps misfolded tau propagate, identifying a more precise starting point for future studies. The discovery is not a treatment for Alzheimer’s, yet, but it finds a potential weakness in one of the molecular processes associated with neurodegeneration, a small target that could have widespread implications for research into diseases that remain difficult to treat.Images Courtesy: istock