What is it about?
Tau aggregates into paired helical filaments (PHF) in Alzheimer’s disease brains. A tau construct (residues 297-391) was recently reported to form PHF-like twisted filaments under high concentrations of magnesium chloride In phosphate buffer. We show that these conditions do not reproduce AD PHF tau. Instead they cause flat ribbons with a distinct molecular structure. We analyze the salt and pH equilibria of this condition, and explain why the non-twisting fibril structure, determined here by solid-state NMR, is stabilized under these conditions.
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Why is it important?
We show that the phosphate buffered MgCl2 condition is impossible due to fundamental salt and pH equilibria. Therefore, to date there is not yet a reproducible condition to make Alzheimer's paired helical filament tau in vitro. The search for such a condition should continue for drug development. This work also highlights that solid-state NMR is uniquely able to solve the structures of non-twisting fibrils, which are difficult to access by cryoEM helical reconstruction.
Perspectives
We hope that this study highlights the importance of understanding and monitoring pH and solubility equilibria during fibril formation. We also call attention to non-twisting filaments, which have been so far neglected because these structures cannot be solved by cryoEM. It is important to document such non-twisting fibrils and their abundance in electron microscopy data. The structures of such non-twisting fibrils can be determined to high resolution by solid-state NMR.
Mei Hong
Massachusetts Institute of Technology
Read the Original
This page is a summary of: Structure of the nonhelical filament of the Alzheimer’s disease tau core, Proceedings of the National Academy of Sciences, October 2023, Proceedings of the National Academy of Sciences,
DOI: 10.1073/pnas.2310067120.
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