title: Mutations in nicastrin protein differentially affect amyloid beta-peptide production and Notch protein processing.
abstract: The γ-secretase complex is responsible for intramembrane processing of over 60 substrates and is involved in Notch signaling as well as in the generation of the amyloid β-peptide (Aβ). Aggregated forms of Aβ have a pathogenic role in Alzheimer disease and, thus, reducing the Aβ levels by inhibiting γ-secretase is a possible treatment strategy for Alzheimer disease. Regrettably, clinical trials have shown that inhibition of γ-secretase results in Notch-related side effects. Therefore, it is of great importance to find ways to inhibit amyloid precursor protein (APP) processing without disturbing vital signaling pathways such as Notch. Nicastrin (Nct) is part of the γ-secretase complex and has been proposed to be involved in substrate recognition and selection. We have investigated how the four evenly spaced and conserved cysteine residues in the Nct ectodomain affect APP and Notch processing. We mutated these cysteines to serines and analyzed them in cells lacking endogenous Nct. We found that two mutants, C213S (C2) and C230S (C3), differentially affected APP and Notch processing. Both the formation of Aβ and the intracellular domain of amyloid precursor protein (AICD) were reduced, whereas the production of Notch intracellular domain (NICD) was maintained on a high level, although C230S (C3) showed impaired complex assembly. Our data demonstrate that single residues in a γ-secretase component besides presenilin are able to differentially affect APP and Notch processing.
authors.affiliation: Department of Neurobiology, Caring Sciences and Society, Karolinska Institutet-Alzheimer Disease Research Center, Karolinska Institutet, Novum, SE-141 86 Stockholm, Sweden.
authors.forename: Annelie
authors.initials: A
authors.lastname: Pamrén
authors.forename: Johanna
authors.initials: J
authors.lastname: Wanngren
authors.forename: Lars O
authors.initials: LO
authors.lastname: Tjernberg
authors.forename: Bengt
authors.initials: B
authors.lastname: Winblad
authors.forename: Ratan
authors.initials: R
authors.lastname: Bhat
authors.forename: Jan
authors.initials: J
authors.lastname: Näslund
authors.forename: Helena
authors.initials: H
authors.lastname: Karlström
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy; D019943:Amino Acid Substitution; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000502:physiology*; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D000818:Animals; D002478:Cells, Cultured; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics
chemical_list: D016229:Amyloid beta-Peptides; D008562:Membrane Glycoproteins; D051880:Receptors, Notch; C413604:nicastrin protein; D053829:Amyloid Precursor Protein Secretases