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Hairpins, beta sheets and fuzzy coats: Tau structure comes into clearer focus

The protein tau is a well-known culprit in Alzheimer’s disease pathology, forming abnormal tangles in the brain that eventually build up to harm communication between neurons. This pathology is also seen in neurodegenerative conditions like chronic traumatic encephalopathy and progressive supranuclear palsy.

Better understanding of the molecular structure of tau is vital for developing future drugs that might inhibit the protein’s misfolding that contributes to Alzheimer’s, dementia and other conditions. A team led by NIA-supported scientists at the Massachusetts Institute of Technology and the University of California at San Francisco has helped solve a big misunderstanding about how recombinant tau — in vitro (test tube) samples of the protein fixed using the polymer heparin for research studies in labs — differs from in vivo tau samples taken after death from the donated brains of study volunteers who had Alzheimer’s disease.

In this study, the researchers took a closer look at the differences in the molecular alignment of tau using various high-tech imaging techniques that allow for near atomic-level resolution pictures of biomolecules. They used a type of tau known as 4R tau which is present in less common Alzheimer’s-related dementias like corticobasal degeneration, frontotemporal dementia and Pick’s disease, and can also help to understand Alzheimer’s.

While it was known that tau misfolds into hairpin shapes that stack and bunch together to form toxic aggregates, the research team hoped to untangle the confusion surrounding the differences in the shape and organization of in vivo and in vitro samples. They found that in vivo tau was made up of long sheets of thousands of protein molecules lined up in a predictable, parallel pattern known as beta-sheets.

4R tau structural model
4R tau solid-state nuclear magnetic resonance image (left) and structural model (right). Credit: Hong Lab, Massachusetts Institute of Technology

Previous studies had concluded that in vitro tau did not have this stable pattern, but instead had many seemingly random shape variations and were therefore poor mimics for in vivo tau samples. Looking closer using powerful and precise imaging technology, the team found that instead, test tube tau samples did in fact have a predictable and stable molecular alignment that repeated regularly. The previous noise or confusion was caused by contamination from the heparin used to stabilize and prep the tau samples for lab use.

The team also found new insights into the motion and shapes of residual amino acids just beyond the stable beta-sheet core of tau. These amino acid remnants appear as tau’s “fuzzy coat” in high-resolution microscope images. This fuzzy coat contains a long flexible region of tau molecules in a similar state to those seen in Alzheimer’s pathology. Better understanding of this region’s structure could help clarify how the early stages of Alzheimer’s pathology impact the brain and focus development of potential therapeutic targets.

The investigators see this as a major breakthrough in understanding and visualizing the structure of tau. They hope this will help improve experimental methods and move the quest for future anti-tau strategies for many neurodegenerative diseases forward.

This research was supported in part by NIA grants AG059661 and AG002132.

Reference: Dregni AJ, et al. In vitro 0N4R tau fibrils contain a monomorphic β-sheet core enclosed by dynamically heterogeneous fuzzy coat segments. Proceedings of the National Academy of Sciences. 2019;116(33):16357-16366. doi: 10.1073/pnas.1906839116.