One of the defining features of Alzheimer’s disease is the buildup of tangled proteins called Tau inside the brain.
As these tangles grow and spread, brain cells lose their ability to function properly.
Understanding exactly how Tau proteins clump together is therefore a major goal for scientists trying to slow or stop the disease.
Tau proteins are unusual. In healthy brain cells, they help support internal structures called microtubules, acting like flexible stabilizers.
But when Tau becomes damaged or misfolded, it can stick to itself and form long fibrils.
These fibrils have a stiff, well-ordered core, surrounded by loose, floppy protein segments. Scientists often describe this outer layer as a “fuzzy coat,” because it constantly moves and changes shape.
Until now, this fuzzy coat has been extremely difficult to study. Most structural techniques work best on rigid, stable molecules.
As a result, researchers have mainly focused on the solid inner core of Tau fibrils, while the fuzzy outer layer—despite making up about 80% of the protein—remained largely unexplored.
Chemists at Massachusetts Institute of Technology have now found a way to change that. Using an advanced form of nuclear magnetic resonance, or NMR, spectroscopy, they were able to map the structure and motion of the fuzzy coat for the first time.
Their findings were published in the Journal of the American Chemical Society.
NMR works by measuring how atomic nuclei respond to magnetic fields, which can reveal how atoms are arranged and how they move.
In this study, the MIT team designed experiments that allowed them to track how magnetic signals travel from the rigid core of a Tau fibril into the flexible outer regions.
By measuring how quickly these signals spread, the researchers could estimate how close different parts of the protein are to one another and how freely they move.
The results revealed an unexpectedly organized picture. The researchers found that the Tau fibril resembles a tightly wrapped burrito. At the center is the rigid core, surrounded by layers of the fuzzy coat. Some of these layers move slowly and stay relatively close to the core, while others—especially the outermost layer—are extremely flexible.
The most mobile regions are rich in an amino acid called proline. These proline-rich segments were once thought to be partly stuck to the core, but the new data show they are highly mobile. This likely happens because they carry positive electrical charges that repel the positively charged core, pushing them outward.
Understanding this structure has important implications for disease. Scientists believe misfolded Tau can act like a template, forcing normal Tau proteins to adopt the same harmful shape. The way the fuzzy coat wraps around the core suggests that new Tau proteins are more likely to attach to the ends of fibrils, allowing them to grow longer, rather than piling onto the sides.
The MIT researchers hope that revealing the fuzzy coat’s structure will help drug developers design molecules that can penetrate this outer layer and break apart Tau tangles.
By finally seeing this elusive part of the protein, scientists are one step closer to understanding—and potentially stopping—the process that drives Alzheimer’s and related brain diseases.
Source: KSR.
