Unraveling the Intricacies: Decoding the Formation of Tau Tangles in the Brain | MIT News

**Understanding the Formation of Tau Fibrils: Potential Target for Drug Intervention**

Many neurodegenerative diseases, such as Alzheimer’s, are characterized by the presence of Tau fibrils. These tangled proteins play a significant role in the progression of the disease. However, a recent study conducted by MIT chemists has shed light on how these fibrils form and has identified a potential target for drug intervention. The findings suggest that one segment of the Tau protein is more flexible than anticipated, influencing the variety of shapes the fibrils can take. Additionally, the researchers discovered that removing the ends of the Tau protein accelerates the formation of fibrils. By identifying a specific sequence of amino acids that aids in the bending of the Tau protein, the researchers believe they have found a promising target for drugs that can impede the formation of Tau tangles.

**Fibril Formation: Uncovering the Link to Neurodegenerative Diseases**

In a healthy brain, Tau proteins bind to microtubules, providing stability. The Tau protein consists of four repeating subunits: R1, R2, R3, and R4. However, in individuals with Alzheimer’s and other neurodegenerative diseases, abnormal versions of Tau form stringy filaments that clump together, eventually leading to the formation of tangles in the brain. Although understanding the structures of these filaments could help unravel the misfolding of abnormal Tau proteins, their inherently disordered framework has made their study challenging. To overcome this obstacle, the MIT researchers employed nuclear magnetic resonance (NMR) to determine certain structures of the filaments, utilizing a recombinant DNA-generated Tau protein.

**Exploring the Influence of End Segments on Fibril Formation**

The researchers focused on the central core of the Tau protein, surrounded by floppy segments whose structures remain unknown. Electron microscopy has demonstrated that these floppy segments form a protective “fuzzy coat” around the central core. To understand the impact of losing these end segments, frequently observed in Alzheimer’s disease, the researchers removed them and examined the resulting protein structure using NMR. The study revealed that without the presence of these floppy segments, the rigid cores of the protein formed filaments with significantly greater ease. This indicates that the fuzzy coat plays a protective role, inhibiting the formation of filaments and potentially safeguarding against neurodegenerative diseases.

**Flexibility of the Tau Protein: Insights into Conformational Changes**

The research also uncovered the structural characteristics of the Tau protein’s repeating subunits. While the R3 repeat, constituting a substantial portion of the rigid core, was found to be highly rigid, the R2 repeat, responsible for the remainder of the core, exhibited greater flexibility. The R2 repeat can adopt different conformations depending on environmental conditions, such as temperature. This conformational flexibility explains the slight structural variations observed in Tau proteins associated with different diseases, including Alzheimer’s, corticobasal degeneration, and argyrophilic grain disease.

**Identifying a Potential Drug Target: The Role of Amino Acids**

Within the R2 repeat, the researchers identified a sequence consisting of six amino acids known to enhance the protein’s flexibility compared to other R segments. This particular region presents a viable target for potential drug intervention aimed at inhibiting Tau fibril formation. By focusing on this conformationally plastic region, small molecule drugs may disrupt the formation of Tau fibrils. Conversely, targeting the stable and rigid R3 region may prove more challenging to disaggregate existing Tau fibrils.

**Future Directions: Advances in Tau Structure Studies**

Moving forward, the researchers plan to investigate whether they can generate Tau structures that closely resemble those found in the brains of patients with Alzheimer’s and other neurodegenerative diseases. This will involve truncating the protein at specific locations or introducing chemical modifications associated with these diseases. By achieving a better understanding of the structures associated with neurodegenerative diseases, researchers can develop new strategies for intervention and treatment.

**Funding and Acknowledgments**

The research was supported by the National Institutes of Health (NIH) and an NIH Ruth L. Kirschstein Individual National Research Service Award.

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