Fluent molecular mixing of Tau isoforms in Alzheimer’s disease neurofibrillary tangles
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s41467-022-30585-0.pdf
Description
Published version
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3.25 MB
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Author(s)
Dregni, Aurelio J
Duan, Pu
Xu, Hong
Changolkar, Lakshmi
El Mammeri, Nadia
Lee, Virginia M-Y
Hong, Mei
Date Issued
May 27, 2022
Journal
Nature Communications
Publisher
Springer Science and Business Media LLC
Citation
Dregni, A.J., Duan, P., Xu, H. et al. Fluent molecular mixing of Tau isoforms in Alzheimer’s disease neurofibrillary tangles. Nat Commun 13, 2967 (2022).
Version
Final published version
Abstract
Alzheimer’s disease (AD) is defined by intracellular neurofibrillary tangles formed by the microtubule-associated protein tau and extracellular plaques formed by the β-amyloid peptide. AD tau tangles contain a mixture of tau isoforms with either four (4R) or three (3R) microtubule-binding repeats. Here we use solid-state NMR to determine how 4R and 3R tau isoforms mix at the molecular level in AD tau aggregates. By seeding differentially isotopically labeled 4R and 3R tau monomers with AD brain-derived tau, we measured intermolecular contacts of the two isoforms. The NMR data indicate that 4R and 3R tau are well mixed in the AD-tau seeded fibrils, with a 60:40 incorporation ratio of 4R to 3R tau and a small homotypic preference. The AD-tau templated 4R tau, 3R tau, and mixed 4R and 3R tau fibrils exhibit no structural differences in the rigid β-sheet core or the mobile domains. Therefore, 4R and 3R tau are fluently recruited into the pathological fold of AD tau aggregates, which may explain the predominance of AD among neurodegenerative disorders.
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DOI of Published Version
https://doi.org/10.1038/s41467-022-30585-0
