title: Modulators of γ-secretase activity can facilitate the toxic side-effects and pathogenesis of Alzheimer's disease.
abstract: BACKGROUND
  Selective modulation of different Aβ products of an intramembrane protease γ-secretase, could be the most promising strategy for development of effective therapies for Alzheimer's disease. We describe how different drug-candidates can modulate γ-secretase activity in cells, by studying how DAPT affects changes in γ-secretase activity caused by gradual increase in Aβ metabolism.
  
  
  RESULTS
  Aβ 1-40 secretion in the presence of DAPT shows biphasic activation-inhibition dose-response curves. The biphasic mechanism is a result of modulation of γ-secretase activity by multiple substrate and inhibitor molecules that can bind to the enzyme simultaneously. The activation is due to an increase in γ-secretase's kinetic affinity for its substrate, which can make the enzyme increasingly more saturated with otherwise sub-saturating substrate. The noncompetitive inhibition that prevails at the saturating substrate can decrease the maximal activity. The synergistic activation-inhibition effects can drastically reduce γ-secretase's capacity to process its physiological substrates. This reduction makes the biphasic inhibitors exceptionally prone to the toxic side-effects and potentially pathogenic. Without the modulation, γ-secretase activity on it physiological substrate in cells is only 14% of its maximal activity, and far below the saturation.
  
  
  CONCLUSIONS
  Presented mechanism can explain why moderate inhibition of γ-secretase cannot lead to effective therapies, the pharmacodynamics of Aβ-rebound phenomenon, and recent failures of the major drug-candidates such as semagacestat. Novel improved drug-candidates can be prepared from competitive inhibitors that can bind to different sites on γ-secretase simultaneously. Our quantitative analysis of the catalytic capacity can facilitate the future studies of the therapeutic potential of γ-secretase and the pathogenic changes in Aβ metabolism.
authors: Medical Biochemistry, PB Rab, Faculty of Medicine, University of Rijeka, Rab, Croatia. zsvedruz@biol.pmf.hr
authors: Željko M
authors: ŽM
authors: Svedružić
authors: Katarina
authors: K
authors: Popović
authors: Vesna
authors: V
authors: Šendula-Jengić
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000009:adverse effects / Q000378:metabolism*; D004151:Dipeptides / Q000009:adverse effects / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D008954:Models, Biological; D010446:Peptide Fragments / Q000009:adverse effects / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D004151:Dipeptides; C419410:N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); D053829:Amyloid Precursor Protein Secretases