Qualitative changes in human γ-secretase underlie familial Alzheimer's disease

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 gamma-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 gamma-secretase activity levels, and therefore, loss of overall (endopeptidase) gamma-secretase function cannot be an essential part of the pathogenic mechanism. In contrast, impaired carboxypeptidase-like activity (gamma-secretase dysfunction) is a constant feature in all FAD brains. Significantly, we demonstrate that pharmacological activation of the carboxypeptidase-like gamma-secretase activity with gamma-secretase modulators alleviates the mutant PSEN pathogenic effects. Most SAD cases display normal endo-and carboxypeptidase-like gamma-secretase activities. However and interestingly, a few SAD patient samples display gamma-secretase dysfunction, suggesting that gamma-secretase may play a role in some SAD cases. In conclusion, our study highlights qualitative shifts in amyloid-beta (A beta) profiles as the common denominator in FAD and supports a model in which the healthy allele contributes with normal A beta products and the diseased allele generates longer aggregation-prone peptides that act as seeds inducing toxic amyloid conformations.