title: γ-Secretase Modulators and APH1 Isoforms Modulate γ-Secretase Cleavage but Not Position of ε-Cleavage of the Amyloid Precursor Protein (APP).
abstract: 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.
authors.affiliation: Department of Neurosciences, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Christian B
authors.initials: CB
authors.lastname: Lessard
authors.affiliation: Department of Neurosciences, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Cottrell
authors.affiliation: Department of Neurosciences, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Maruyama
authors.affiliation: Department of Neurosciences, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Suraj
authors.initials: S
authors.lastname: Suresh
authors.affiliation: Center for Translational Research in Neurodegenerative Disease, Department of Neuroscience, College of Medicine, University of Florida, Florida, United States of America.
authors.forename: Todd E
authors.initials: TE
authors.lastname: Golde
authors.affiliation: Department of Neurosciences, University of California San Diego, La Jolla, California, United States of America.|Departments of Medicine and Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
authors.forename: Edward H
authors.initials: EH
authors.lastname: Koo
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016466:CHO Cells; D020134:Catalytic Domain; D003412:Cricetulus; D010450:Endopeptidases; D011345:Fenofibrate / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D047468:Immunoprecipitation; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D009154:Mutation; D010446:Peptide Fragments / Q000378:metabolism; D010447:Peptide Hydrolases / Q000235:genetics / Q000502:physiology*; D020033:Protein Isoforms / Q000502:physiology; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
chemical_list: D016564:Amyloid beta-Protein Precursor; D008565:Membrane Proteins; D010446:Peptide Fragments; D020033:Protein Isoforms; C543304:amyloid beta-protein precursor C-terminal fragment beta, human; C475154:APH1A protein, human; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D010447:Peptide Hydrolases; D011345:Fenofibrate