Fluent molecular mixing of Tau isoforms in Alzheimer's disease neurofibrillary tangles.
Nat Commun
; 13(1): 2967, 2022 05 27.
Article
em En
| MEDLINE
| ID: mdl-35624093
ABSTRACT
Alzheimer's disease (AD) is defined by intracellular neurofibrillary tangles formed by the microtubule-associated protein tau and extracellular plaques formed by the ß-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 6040 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 ß-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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Emaranhados Neurofibrilares
/
Doença de Alzheimer
Limite:
Humans
Idioma:
En
Revista:
Nat Commun
Assunto da revista:
BIOLOGIA
/
CIENCIA
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Estados Unidos