engleski

Decrease in catalytic capacity of gamma- 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 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.

Early diagnostics ; Familiar Alzheimer's disease mutations ; Pathogenesis

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