Alzheimer's disease-associated mutations increase amyloid precursor protein resistance to γ-secretase cleavage and the Aß42/Aß40 ratio.
Cell Discov
; 2: 16026, 2016.
Article
en En
| MEDLINE
| ID: mdl-27625790
ABSTRACT
Mutations in the amyloid precursor protein (APP) gene and the aberrant cleavage of APP by γ-secretase are associated with Alzheimer's disease (AD). Here we have developed a simple and sensitive cell-based assay to detect APP cleavage by γ-secretase. Unexpectedly, most familial AD (FAD)-linked APP mutations make APP partially resistant to γ-secretase. Mutations that alter residues N terminal to the γ-secretase cleavage site Aß42 have subtle effects on cleavage efficiency and cleavage-site selectivity. In contrast, mutations that alter residues C terminal to the Aß42 site reduce cleavage efficiency and dramatically shift cleavage-site specificity toward the aggregation-prone Aß42. Moreover, mutations that remove positive charge at residue 53 greatly reduce the APP cleavage by γ-secretase. These results suggest a model of γ-secretase substrate recognition, in which the APP region C terminal to the Aß42 site and the positively charged residue at position 53 are the primary determinants for substrate binding and cleavage-site selectivity. We further demonstrate that this model can be extended to γ-secretase processing of notch receptors, a family of highly conserved cell-surface signaling proteins.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Tipo de estudio:
Risk_factors_studies
Idioma:
En
Revista:
Cell Discov
Año:
2016
Tipo del documento:
Article