Abstract:
Researchers from Northwestern University and the University of California, Santa Barbara found that when tau proteins form pathological fibers, they may first bind to each other through a specific region stabilized by water molecules, and then gradually complete structural matching. This study, published in the Proceedings of the National Academy of Sciences, provides new mechanistic clues for understanding how abnormal proteins in tauopathies such as Alzheimer's disease "recruit" normal tau proteins, and also points to a potential target for intervention.
Tau protein is usually involved in maintaining the internal structure of nerve cells. However, in tauopathies such as Alzheimer's disease and frontotemporal dementia, tau may fold abnormally and aggregate into fibers and neurofibrillary tangles. Existing pathological fibers can also serve as "seeds" to attract new tau molecules to join and induce them to adopt similar abnormal forms, allowing the aggregation to continue to extend. The research team tried to explain how these tau molecules, which lack a fixed structure themselves, can be precisely aligned at the end of the fiber and grow along the original structure.
The researchers used nuclear magnetic resonance to track the changes in tau fragments when they meet existing fibers in real time, and combined molecular dynamics simulations to analyze water molecules on the fiber surface. The experiment focused on an engineered tau fragment consisting of 19 amino acids, covering positions 295 to 313, and carrying the disease-associated P301L mutation. The results showed that the hydrophobic region near position 300 was a preferential contact point: the tau molecules "parked" here first, and then the rest of the tau molecules gradually folded and embedded into the existing fibers. The researchers described this process as "docking-locking."
Water molecules around this hot spot form a dynamic and ordered hydration layer, enveloping hydrophobic areas that are not easily compatible with water. The research team believes that when another tau molecule approaches, local water molecules are expelled, bringing the two binding areas into contact and aligning, which drives the fiber to elongate. In other words, water is not simply a background environment, but may be involved in the initial binding steps of pathological protein aggregation.
To test whether this position is critical, the researchers performed site-specific labeling on different parts of the tau fragment. After blocking the hot spot, the template-induced aggregation was significantly disrupted and the fibers formed were shorter; similar treatment at other locations away from the hot spot had much smaller effects. The findings suggest that designing molecules targeting this binding region may be expected to slow down the extension of abnormal tau fibers or help develop diagnostic tools in the future.
However, this work is currently basic research and does not prove that blocking this site can prevent or treat Alzheimer's disease. The experiments mainly used short tau fragments with mutations and fibers prepared in vitro, which have not been verified in patients, animal models or clinical treatments. Whether this hotspot is always the same in different tau conformations and different tau protein diseases remains to be confirmed. The research team stated that it is necessary to test whether this mechanism can be applied to more complete tau proteins and explore whether this process can be safely intervened in the brain.
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