Year: 2022
Type: article
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.
Source: Nature Communications
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,890
Awards: Frontotemporal Dementias: Genotypes and Phenotypes, Molecular structures of tau aggregates studied by solid-state NMR, MIT/Harvard Center for Magnetic Resonance, Investigation of Seeded Alzheimer's Disease Tau Fibrils with Solid-State NMR, G6017699117, G6253809156, G6889702124, G9000012777, G9000096719, G9000202055, Pathogenesis of Tauopathies, Tau structure and dynamics in Alzheimer's disease
OpenAlex ID: W4281624589