1. Qualitative changes in human ?-secretase underlie familial Alzheimer's disease
- Author
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Szaruga M., Veugelen S., Benurwar M., Lismont S., Sepulveda-Falla D., Lleo A., Ryan N.S., Lashley T., Fox N.C., Murayama S., Gijsen H., De Strooper B., and Chávez-Gutiérrez L.
- Subjects
Male ,amyloid precursor protein ,Carboxypeptidases ,Western blotting ,Amyloid beta-Protein Precursor ,middle aged ,pathogenicity ,animal ,genetics ,gene mutation ,familial Alzheimer disease ,Cells, Cultured ,familial disease ,Mice, Knockout ,clinical article ,adult ,amyloid ,protein processing ,Brain ,cell communication ,protein function ,carboxypeptidase ,enzyme activity ,aged ,female ,priority journal ,Alzheimer disease ,onset age ,intron ,secretase ,Blotting, Western ,gamma secretase ,Article ,PSEN1 protein, human ,presenilin 1 ,Presenilin-1 ,qualitative analysis ,Animals ,Humans ,controlled study ,human ,protein expression ,enzyme analysis ,cell culture ,heterozygote ,human tissue ,Mutation ,pathology ,Amyloid Precursor Protein Secretases ,knockout mouse ,metabolism - Abstract
Presenilin (PSEN) pathogenic mutations cause familial Alzheimer's disease (AD [FAD]) in an autosomal-dominant manner. The extent to which the healthy and diseased alleles influence each other to cause neurodegeneration remains unclear. In this study, we assessed ?-secretase activity in brain samples from 15 nondemented subjects, 22 FAD patients harboring nine different mutations in PSEN1, and 11 sporadic AD (SAD) patients. FAD and control brain samples had similar overall ?-secretase activity levels, and therefore, loss of overall (endopeptidase) ?-secretase function cannot be an essential part of the pathogenic mechanism. In contrast, impaired carboxypeptidase-like activity (?-secretase dysfunction) is a constant feature in all FAD brains. Significantly, we demonstrate that pharmacological activation of the carboxypeptidase-like ?-secretase activity with ?-secretase modulators alleviates the mutant PSEN pathogenic effects. Most SAD cases display normal endo- and carboxypeptidase- like ?-secretase activities. However and interestingly, a few SAD patient samples display ?-secretase dysfunction, suggesting that ?-secretase may play a role in some SAD cases. In conclusion, our study highlights qualitative shifts in amyloid-ß (Aß) profiles as the common denominator in FAD and supports a model in which the healthy allele contributes with normal Aß products and the diseased allele generates longer aggregation-prone peptides that act as seeds inducing toxic amyloid conformations. © 2015 Szaruga et al.
- Published
- 2015