title: Decrease in catalytic capacity of γ-secretase can facilitate pathogenesis in sporadic and Familial Alzheimer's disease.
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.
authors.affiliation: 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.
authors.forename: Željko M
authors.initials: ŽM
authors.lastname: Svedružić
authors.affiliation: Neurology and Geriatrics, PB Rab, Faculty of Medicine, University of Rijeka, Rab, Croatia.
authors.forename: Katarina
authors.initials: K
authors.lastname: Popović
authors.affiliation: 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.
authors.forename: Vesna
authors.initials: V
authors.lastname: Šendula-Jengić
mesh_terms: D000328:Adult; D000544:Alzheimer Disease / Q000097:blood / Q000201:enzymology*; D053829:Amyloid Precursor Protein Secretases / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D002460:Cell Line; D006801:Humans; D051379:Mice; D008875:Middle Aged; D020125:Mutation, Missense; D053764:Presenilin-1 / Q000235:genetics
chemical_list: D016229:Amyloid beta-Peptides; D015415:Biomarkers; D053764:Presenilin-1; D053829:Amyloid Precursor Protein Secretases
keywords: Early diagnostics; Familiar Alzheimer's disease mutations; Pathogenesis