γ-Secretase Modulators and APH1 Isoforms Modulate γ-Secretase Cleavage but Not Position of ε-Cleavage of the Amyloid Precursor Protein (APP)
Copyright policy )γ-Secretase Modulators and APH1 Isoforms Modulate γ-Secretase Cleavage but Not Position of ε-Cleavage of the Amyloid Precursor Protein (APP)
The relative increase in Aβ42 peptides from familial Alzheimer disease (FAD) linked APP and PSEN mutations can be related to changes in both ε-cleavage site utilization and subsequent step-wise cleavage. Cleavage at the ε-site releases the amyloid precursor protein (APP) intracellular domain (AICD), and perturbations in the position of ε-cleavage are closely associated with changes in the profile of amyloid β-protein (Aβ) species that are produced and secreted. The mechanisms by which γ-secretase modulators (GSMs) or FAD mutations affect the various γ-secretase cleavages to alter the generation of Aβ peptides have not been fully elucidated. Recent studies suggested that GSMs do not modulate ε-cleavage of APP, but the data were derived principally from recombinant truncated epitope tagged APP substrate. Here, using full length APP from transfected cells, we investigated whether GSMs modify the ε-cleavage of APP under more native conditions. Our results confirmed the previous findings that ε-cleavage is insensitive to GSMs. In addition, fenofibrate, an inverse GSM (iGSM), did not alter the position or kinetics of ε-cleavage position in vitro. APH1A and APH1B, a subunit of the γ-secretase complex, also modulated Aβ42/Aβ40 ratio without any alterations in ε-cleavage, a result in contrast to what has been observed with PS1 and APP FAD mutations. Consequently, GSMs and APH1 appear to modulate γ-secretase activity and Aβ42 generation by altering processivity but not ε-cleavage site utilization.
- University of Florida United States
- National University of Singapore Singapore
- University of California-San Diego Finland
- National University of Singapore Libraries Singapore
- University of California, San Diego United States
570, Science, 610, CHO Cells, Amyloid beta-Protein Precursor, Cricetulus, Fenofibrate, Catalytic Domain, Endopeptidases, Animals, Humans, Immunoprecipitation, Protein Isoforms, Q, R, Membrane Proteins, Peptide Fragments, HEK293 Cells, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Mutation, Medicine, Amyloid Precursor Protein Secretases, Research Article, Peptide Hydrolases
570, Science, 610, CHO Cells, Amyloid beta-Protein Precursor, Cricetulus, Fenofibrate, Catalytic Domain, Endopeptidases, Animals, Humans, Immunoprecipitation, Protein Isoforms, Q, R, Membrane Proteins, Peptide Fragments, HEK293 Cells, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Mutation, Medicine, Amyloid Precursor Protein Secretases, Research Article, Peptide Hydrolases
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