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How Tau tangles form in the brain

MIT chemists have made significant progress in understanding the formation of Tau fibrils, which are tangled proteins associated with neurodegenerative diseases like Alzheimer’s.

The researchers discovered that a flexible segment of the Tau protein contributes to the varied shapes of the fibrils, and they found that fibril formation is more likely when the ends of the Tau protein are cleaved off. The team also identified a sequence of amino acids that could serve as a target for drugs to disrupt the formation of Tau tangles. Their study, published in Science Advances, sheds light on the structures and potential vulnerabilities of Tau fibrils, offering insights for future therapeutic interventions.

Using nuclear magnetic resonance (NMR), the researchers analyzed the structures of Tau fibrils. They focused on the central core of the Tau protein, where rigid folded protein strands called beta sheets create a structure surrounded by flexible segments. By removing the flexible segments, the researchers observed that the rigid cores formed fibrils more easily, suggesting that the flexible segments play a protective role in preventing fibril formation.

Additionally, the study revealed that different environmental conditions, such as temperature, can influence the conformation of the Tau protein. The R2 repeat, which makes up part of the core, was found to exhibit different conformations, including straight and hinged segments, depending on the conditions. This flexibility may account for structural differences observed in Tau proteins associated with various diseases.

Within the R2 repeat, the researchers identified a sequence of six amino acids that contribute to the protein’s flexibility. This region could be a potential target for small molecule drugs aimed at inhibiting Tau fibril formation.

The researchers plan to further investigate the structures of Tau proteins found in patients with Alzheimer’s and other neurodegenerative diseases. By truncating the protein or introducing specific chemical modifications, they aim to generate Tau structures that closely resemble those found in diseased brains.

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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