title: Aβ42 oligomers modulate β-secretase through an XBP-1s-dependent pathway involving HRD1.
abstract: The aspartyl protease β-site APP cleaving enzyme, BACE1, is the rate-limiting enzyme involved in the production of amyloid-β peptide, which accumulates in both sporadic and familial cases of Alzheimer's disease and is at the center of gravity of the amyloid cascade hypothesis. In this context, unravelling the molecular mechanisms controlling BACE1 expression and activity in both physiological and pathological conditions remains of major importance. We previously demonstrated that Aβ controlled BACE1 transcription in an NFκB-dependent manner. Here, we delineate an additional cellular pathway by which natural and synthetic Aβ42 oligomers enhance active X-box binding protein XBP-1s. XBP-1s lowers BACE1 expression and activity indirectly, via the up-regulation of the ubiquitin-ligase HRD1 that acts as an endogenous down-regulator of BACE1. Thus, we delineate a novel pathway by which cells could compensate for Aβ42 oligomers production and thus, associated toxicity, by triggering a compensatory mechanism aimed at lowering BACE-1-mediated Aβ production by a molecular cascade involving XBP-1s and HRD1. It thus identifies HRD1 as a potential target for a novel Aβ-centered therapeutic strategy.
authors.affiliation: Université Côte d'Azur, INSERM, CNRS, IPMC, France, Laboratory of excellence DistALZ, 660 route des Lucioles, 06560, Sophia-Antipolis, Valbonne, France.
authors.forename: Yannis
authors.initials: Y
authors.lastname: Gerakis
authors.affiliation: Université Côte d'Azur, INSERM, CNRS, IPMC, France, Laboratory of excellence DistALZ, 660 route des Lucioles, 06560, Sophia-Antipolis, Valbonne, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Dunys
authors.affiliation: Université Côte d'Azur, INSERM, CNRS, IPMC, France, Laboratory of excellence DistALZ, 660 route des Lucioles, 06560, Sophia-Antipolis, Valbonne, France.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Bauer
authors.affiliation: Université Côte d'Azur, INSERM, CNRS, IPMC, France, Laboratory of excellence DistALZ, 660 route des Lucioles, 06560, Sophia-Antipolis, Valbonne, France.
authors.forename: Fréderic
authors.initials: F
authors.lastname: Checler
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000235:genetics* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D003513:Cycloheximide / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology*; D010957:Plasmids / Q000737:chemistry / Q000378:metabolism; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism; D000071717:X-Box Binding Protein 1 / Q000235:genetics* / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; C489427:MYC protein, human; D010446:Peptide Fragments; D011500:Protein Synthesis Inhibitors; D016271:Proto-Oncogene Proteins c-myc; D011993:Recombinant Fusion Proteins; D000071717:X-Box Binding Protein 1; C000605544:Xbp1 protein, mouse; C075222:amyloid beta-protein (1-42); D003513:Cycloheximide; D008156:Luciferases; C482345:SYVN1 protein, human; D044767:Ubiquitin-Protein Ligases; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human