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

• Published in: Molecular and cellular neuroscience 2015-07, Vol.67, p.55-65
• Main Authors: Svedružić, Željko M., Popović, Katarina, Šendula-Jengić, Vesna
• Format: Article
• Language: English
• Subjects: Adult; Alzheimer Disease - blood; Alzheimer Disease - enzymology; Amyloid beta-Peptides - metabolism; Amyloid Precursor Protein Secretases - blood; Amyloid Precursor Protein Secretases - genetics; Amyloid Precursor Protein Secretases - metabolism; Animals; Biomarkers - blood; Case-Control Studies; Cell Line; Early diagnostics; Familiar Alzheimer's disease mutations; Humans; Mice; Middle Aged; Mutation, Missense; Pathogenesis; Presenilin-1 - genetics
• ISSN: 1044-7431; 1095-9327
• DOI: 10.1016/j.mcn.2015.06.002

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. 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. 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. •We do not know how changes in γ-secretase activity can support pathogenesis in Alzheimer's disease.•Confusingly both increase and decrease in γ-secretase's activity can be observed in pathogenesis.•The decrease in γ-secretase capacity to process its substrate is a good indicator of pathogenic events.•Measurements of γ-secretase capacity to process its substrate can be used as an early diagnostic tool.•Measurements of γ-secretase capacity to process its substrate can be used in the development of drugs.