Alzheimer's disease-associated mutations increase amyloid precursor protein resistance to ?-secretase cleavage and the A?42/A?40 ratio.

ABSTRACT: Mutations in the amyloid precursor protein (APP) gene and the aberrant cleavage of APP by ?-secretase are associated with Alzheimer's disease (AD). Here we have developed a simple and sensitive cell-based assay to detect APP cleavage by ?-secretase. Unexpectedly, most familial AD (FAD)-linked APP mutations make APP partially resistant to ?-secretase. Mutations that alter residues N terminal to the ?-secretase cleavage site A?42 have subtle effects on cleavage efficiency and cleavage-site selectivity. In contrast, mutations that alter residues C terminal to the A?42 site reduce cleavage efficiency and dramatically shift cleavage-site specificity toward the aggregation-prone A?42. Moreover, mutations that remove positive charge at residue 53 greatly reduce the APP cleavage by ?-secretase. These results suggest a model of ?-secretase substrate recognition, in which the APP region C terminal to the A?42 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 ?-secretase processing of notch receptors, a family of highly conserved cell-surface signaling proteins.

SUBMITTER: Xu TH 

PROVIDER: S-EPMC4994064 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature