Decrease in catalytic capacity of γ-secretase can facilitate pathogenesis in sporadic and Familial Alzheimer's disease

Background: Alzheimer's disease can be a result of an age-induced disparity between increase in cellular metabolism of A beta peptides and decrease in maximal activity of a membrane-embedded protease gamma-secretase. Results: We compared activity of WT gamma-secretase with the activity of 6 FAD mutants in its presenilin-1 component and 5 FAD mutants in A beta-part of its APP substrate (Familial Alzheimer's disease). All 11 FAD mutations show linear correlation between the decrease in maximal activity and the clinically observed age-of-onset and age-of-death. Biphasic-inhibitors showed that a higher ratio between physiological A beta-production and the maximal activity of gamma-secretase can be observed in cells that can facilitate pathogenic changes in A beta-products. For example, A beta production in cells with WT gamma-secretase is at 11% of its maximal activity, with delta-exon-9 mutant at 26%, while with M139V mutant is at 28% of the maximal activity. In the same conditions, G384A mutant is fully saturated and at its maximal activity. Similarly, A beta production in cells with gamma-secretase complex carrying Aph1A(L) component is 12% of its maximal activity, while in cells with Aph1B complex is 26% of its maximal activity. Similar to the cell-based studies, clinical studies of biphasic dose-response in plasma samples of 54 healthy individuals showed variable ratios between physiological A beta production and the maximal activity of gamma-secretase. Conclusions: The increase in the ratio between physiological A beta production and maximal activity of gamma-secretase can be an early sign of pathogenic processes in enzyme-based, cell-based, and clinical studies of sporadic and Familiar Alzheimer's disease. Crown Copyright (C) 2015 Published by Elsevier Inc. All rights reserved.