title: Nuclear translocation uncovers the amyloid peptide Aβ42 as a regulator of gene transcription.
abstract: Although soluble species of the amyloid-β peptide Aβ42 correlate with disease symptoms in Alzheimer disease, little is known about the biological activities of amyloid-β (Aβ). Here, we show that Aβ peptides varying in lengths from 38 to 43 amino acids are internalized by cultured neuroblastoma cells and can be found in the nucleus. By three independent methods, we demonstrate direct detection of nuclear Aβ42 as follows: (i) biochemical analysis of nuclear fractions; (ii) detection of biotin-labeled Aβ in living cells by confocal laser scanning microscopy; and (iii) transmission electron microscopy of Aβ in cultured cells, as well as brain tissue of wild-type and transgenic APPPS1 mice (overexpression of amyloid precursor protein and presenilin 1 with Swedish and L166P mutations, respectively). Also, this study details a novel role for Aβ42 in nuclear signaling, distinct from the amyloid precursor protein intracellular domain. Chromatin immunoprecipitation showed that Aβ42 specifically interacts as a repressor of gene transcription with LRP1 and KAI1 promoters. By quantitative RT-PCR, we confirmed that mRNA levels of the examined candidate genes were exclusively decreased by the potentially neurotoxic Aβ42 wild-type peptide. Shorter peptides (Aβ38 or Aβ40) and other longer peptides (nontoxic Aβ42 G33A substitution or Aβ43) did not affect mRNA levels. Overall, our data indicate that the nuclear translocation of Aβ42 impacts gene regulation, and deleterious effects of Aβ42 in Alzheimer disease pathogenesis may be influenced by altering the expression profiles of disease-modifying genes.
authors.affiliation: From the Institut fuer Chemie und Biochemie, Freie Universitaet Berlin, 14195 Berlin, Germany, the Department of Pharmacology and Therapeutics, Faculty of Medicine, McGill University, Montreal, Quebec H3G 0B1, Canada.
authors.forename: Christian
authors.initials: C
authors.lastname: Barucker
authors.affiliation: From the Institut fuer Chemie und Biochemie, Freie Universitaet Berlin, 14195 Berlin, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Harmeier
authors.affiliation: the Institute of Clinical Chemistry and Pathobiochemistry, Charite-Campus Benjamin Franklin, 12203 Berlin, Germany.
authors.forename: Joerg
authors.initials: J
authors.lastname: Weiske
authors.affiliation: the Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
authors.forename: Beatrix
authors.initials: B
authors.lastname: Fauler
authors.affiliation: the Institute of Clinical Chemistry and Pathobiochemistry, Charite-Campus Benjamin Franklin, 12203 Berlin, Germany, the Institute of Biochemistry II, Jena University Hospital, Friedrich Schiller University, 07743 Jena, Germany, and.
authors.forename: Kai Frederik
authors.initials: KF
authors.lastname: Albring
authors.affiliation: the Department of Neuropathology.
authors.forename: Stefan
authors.initials: S
authors.lastname: Prokop
authors.affiliation: Institute of Medical Physics and Biophysics, Charite-Universitätsmedizin Berlin, 10117 Berlin, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Hildebrand
authors.affiliation: the Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
authors.forename: Rudi
authors.initials: R
authors.lastname: Lurz
authors.affiliation: the Department of Neuropathology.
authors.forename: Frank L
authors.initials: FL
authors.lastname: Heppner
authors.affiliation: the Institute of Clinical Chemistry and Pathobiochemistry, Charite-Campus Benjamin Franklin, 12203 Berlin, Germany, the Institute of Biochemistry II, Jena University Hospital, Friedrich Schiller University, 07743 Jena, Germany, and.
authors.forename: Otmar
authors.initials: O
authors.lastname: Huber
authors.affiliation: From the Institut fuer Chemie und Biochemie, Freie Universitaet Berlin, 14195 Berlin, Germany, the Department of Pharmacology and Therapeutics, Faculty of Medicine, McGill University, Montreal, Quebec H3G 0B1, Canada, gerhard.multhaup@mcgill.ca.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Multhaup
mesh_terms: D021581:Active Transport, Cell Nucleus; D000544:Alzheimer Disease / Q000378:metabolism; D019943:Amino Acid Substitution; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008958:Models, Molecular; D016297:Mutagenesis, Site-Directed; D009474:Neurons / Q000378:metabolism / Q000648:ultrastructure; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D053764:Presenilin-1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D055503:Protein Multimerization; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D055672:Static Electricity
chemical_list: C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; D012333:RNA, Messenger; D011994:Recombinant Proteins; C075222:amyloid beta-protein (1-42)
keywords: Alzheimer Disease; Amyloid; Amyloid β42 Toxicity; Amyloid β42-Chromatin Interaction; Chromatin Immunoprecipitation (ChiP); Gene Regulation; Nuclear Amyloid β Peptides; RNA