A common antigenic motif recognized by naturally occurring human VH5-51/VL4-1 anti-tau antibodies with distinct functionalities.
Acta Neuropathol Commun
; 6(1): 43, 2018 05 31.
Article
em En
| MEDLINE
| ID: mdl-29855358
ABSTRACT
Misfolding and aggregation of tau protein are closely associated with the onset and progression of Alzheimer's Disease (AD). By interrogating IgG+ memory B cells from asymptomatic donors with tau peptides, we have identified two somatically mutated VH5-51/VL4-1 antibodies. One of these, CBTAU-27.1, binds to the aggregation motif in the R3 repeat domain and blocks the aggregation of tau into paired helical filaments (PHFs) by sequestering monomeric tau. The other, CBTAU-28.1, binds to the N-terminal insert region and inhibits the spreading of tau seeds and mediates the uptake of tau aggregates into microglia by binding PHFs. Crystal structures revealed that the combination of VH5-51 and VL4-1 recognizes a common Pro-Xn-Lys motif driven by germline-encoded hotspot interactions while the specificity and thereby functionality of the antibodies are defined by the CDR3 regions. Affinity improvement led to improvement in functionality, identifying their epitopes as new targets for therapy and prevention of AD.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Imunoglobulina G
/
Linfócitos B
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Proteínas tau
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Cadeias Pesadas de Imunoglobulinas
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Cadeias Leves de Imunoglobulina
Tipo de estudo:
Prognostic_studies
Limite:
Adolescent
/
Adult
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Aged
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Female
/
Humans
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Male
/
Middle aged
Idioma:
En
Revista:
Acta Neuropathol Commun
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
Holanda