Tau protein clumping, which forms tangled fibrils in the brain, is a characteristic of Alzheimer's disease. The severity of clumping correlates with disease progression. Tau protein, also linked to other neurodegenerative diseases, is normally unstructured but adopts a pathological state with a rigid core surrounded by disordered "fuzzy coat" segments. This fuzzy coat influences Tau's interactions with other molecules.
MIT chemists have utilized nuclear magnetic resonance (NMR) spectroscopy to determine the structure of this fuzzy coat, a first-time achievement. This finding is expected to assist in the development of drugs aimed at preventing Tau buildup in the brain. Mei Hong, an MIT professor of chemistry and senior author, stated that drugs intended to disaggregate Tau fibrils would need to penetrate this fuzzy coat.
Jia Yi Zhang, an MIT graduate student, is the lead author of the paper published in the Journal of the American Chemical Society, with former MIT postdoc Aurelio Dregni also contributing.
Analyzing the Fuzzy Coat
In a healthy brain, Tau proteins stabilize microtubules, which provide cellular structure. However, misfolded or altered Tau proteins form clumps that contribute to neurodegenerative conditions like Alzheimer's and frontotemporal dementia.
Characterizing the structure of Tau tangles has been challenging because approximately 80% of the protein is in the highly disordered fuzzy coat. This fuzzy coat surrounds a rigid inner core composed of beta sheets, whose structure Hong's team had previously analyzed using NMR. Researchers previously focused on the rigid core, as standard techniques like cryoelectron microscopy and X-ray crystallography could not capture the dynamic disordered segments.
In the current study, researchers developed NMR techniques to investigate the entire Tau protein. One experiment involved magnetizing protons in rigid amino acids and measuring the transfer of magnetization to mobile amino acids, tracking the movement from rigid to floppy segments and vice versa. This method allowed for estimating the proximity between rigid and mobile segments. The team also measured the differing degrees of movement among amino acids in the fuzzy coat.
Hong stated that an NMR-based technology has been developed to examine the fuzzy coat of a full-length Tau fibril, enabling the capture of both dynamic regions and the rigid core.
Protein Dynamics
For the specific fibril studied, the Tau protein's overall structure, which includes about 10 domains, was found to resemble a burrito, with layers of the fuzzy coat enveloping the rigid core. Based on protein dynamics measurements, segments were categorized into three groups: the rigid core was surrounded by regions of intermediate mobility, with the most dynamic segments forming the outermost layer.
The most dynamic segments of the fuzzy coat are rich in proline, an amino acid. These prolines are located near the amino acids forming the rigid core and were previously thought to be partially immobilized. Their high mobility suggests that these positively charged proline-rich regions are repelled by the positive charges of the amino acids within the rigid core.
This structural model offers insight into how Tau proteins form tangles in the brain. It is hypothesized that misfolded Tau proteins act as templates, inducing normal Tau proteins to adopt an abnormal structure, similar to prions. The wrapping of the fuzzy coat around the rigid core suggests that normal Tau proteins are more likely to add to the ends of existing short filaments, extending the fibrils.
The researchers plan to investigate whether normal Tau proteins can be stimulated to assemble into Alzheimer's-type fibrils using misfolded Tau proteins from Alzheimer's patients as a template. The National Institutes of Health funded the research.