Željko M Svedružić1, Katarina Popović2, Vesna Šendula-Jengić3. 1. Medical Biochemistry, PB Rab, Faculty of Medicine, University of Rijeka, Rab, Croatia; Department of Biotechnology, University of Rijeka, Rijeka, Croatia. Electronic address: zsvedruz@biol.pmf.hr. 2. Neurology and Geriatrics, PB Rab, Faculty of Medicine, University of Rijeka, Rab, Croatia. 3. Medical Biochemistry, PB Rab, Faculty of Medicine, University of Rijeka, Rab, Croatia; Neurology and Geriatrics, PB Rab, Faculty of Medicine, University of Rijeka, Rab, Croatia.
Abstract
BACKGROUND: Alzheimer's disease can be a result of an age-induced disparity between increase in cellular metabolism of Aβ peptides and decrease in maximal activity of a membrane-embedded protease γ-secretase. RESULTS: We compared activity of WT γ-secretase with the activity of 6 FAD mutants in its presenilin-1 component and 5 FAD mutants in Aβ-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 Aβ-production and the maximal activity of γ-secretase can be observed in cells that can facilitate pathogenic changes in Aβ-products. For example, Aβ production in cells with WT γ-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, Aβ production in cells with γ-secretase complex carrying Aph1AL 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 Aβ production and the maximal activity of γ-secretase. CONCLUSIONS: The increase in the ratio between physiological Aβ production and maximal activity of γ-secretase can be an early sign of pathogenic processes in enzyme-based, cell-based, and clinical studies of sporadic and Familiar Alzheimer's disease.
BACKGROUND:Alzheimer's disease can be a result of an age-induced disparity between increase in cellular metabolism of Aβ peptides and decrease in maximal activity of a membrane-embedded protease γ-secretase. RESULTS: We compared activity of WT γ-secretase with the activity of 6 FAD mutants in its presenilin-1 component and 5 FAD mutants in Aβ-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 Aβ-production and the maximal activity of γ-secretase can be observed in cells that can facilitate pathogenic changes in Aβ-products. For example, Aβ production in cells with WT γ-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, Aβ production in cells with γ-secretase complex carrying Aph1AL 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 Aβ production and the maximal activity of γ-secretase. CONCLUSIONS: The increase in the ratio between physiological Aβ production and maximal activity of γ-secretase can be an early sign of pathogenic processes in enzyme-based, cell-based, and clinical studies of sporadic and Familiar Alzheimer's disease.