title: Alzheimer amyloid peptide aβ42 regulates gene expression of transcription and growth factors.
abstract: The pathogenesis of Alzheimer's disease (AD) is characterized by the aggregation of amyloid-β (Aβ) peptides leading to deposition of senile plaques and a progressive decline of cognitive functions, which currently remains the main criterion for its diagnosis. Robust biomarkers for AD do not yet exist, although changes in the cerebrospinal fluid levels of tau and Aβ represent promising candidates in addition to brain imaging and genetic risk profiling. Although concentrations of soluble Aβ42 correlate with symptoms of AD, less is known about the biological activities of Aβ peptides which are generated from the amyloid-β protein precursor. An unbiased DNA microarray study showed that Aβ42, at sub-lethal concentrations, specifically increases expression of several genes in neuroblastoma cells, notably the insulin-like growth factor binding proteins 3 and 5 (IGFBP3/5), the transcription regulator inhibitor of DNA binding, and the transcription factor Lim only domain protein 4. Using qRT-PCR, we confirmed that mRNA levels of the identified candidate genes were exclusively increased by the potentially neurotoxic Aβ42 wild-type peptide, as both the less toxic Aβ40 and a non-toxic substitution peptide Aβ42 G33A did not affect mRNA levels. In vivo immunohistochemistry revealed a corresponding increase in both hippocampal and cortical IGFBP5 expression in an AD mouse model. Proteomic analyses of human AD cerebrospinal fluid displayed increased in vivo concentrations of IGFBPs. IGFBPs and transcription factors, as identified here, are modulated by soluble Aβ42 and may represent useful early biomarkers.
authors.affiliation: Institut fuer Chemie und Biochemie, Freie Universitaet Berlin, Berlin, Germany Department of Pharmacology & Therapeutics, McGill University, Montreal, QC, Canada.
authors.forename: Christian
authors.initials: C
authors.lastname: Barucker
authors.affiliation: Bayer Pharma AG, Global Drug Discovery, Berlin, Germany.
authors.forename: Anette
authors.initials: A
authors.lastname: Sommer
authors.affiliation: Bayer Pharma AG, Global Drug Discovery, Berlin, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Beckmann
authors.affiliation: Institut fuer Chemie und Biochemie, Freie Universitaet Berlin, Berlin, Germany.
authors.forename: Murat
authors.initials: M
authors.lastname: Eravci
authors.affiliation: Institut fuer Chemie und Biochemie, Freie Universitaet Berlin, Berlin, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Harmeier
authors.affiliation: Department of Psychiatry and Psychotherapy, Campus Benjamin Franklin, Charite-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Carola G
authors.initials: CG
authors.lastname: Schipke
authors.affiliation: Bayer Pharma AG, Global Drug Discovery, Berlin, Germany.
authors.forename: Damian
authors.initials: D
authors.lastname: Brockschnieder
authors.affiliation: Bayer Pharma AG, Global Drug Discovery, Berlin, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Dyrks
authors.affiliation: Institut fuer Chemie und Biochemie, Freie Universitaet Berlin, Berlin, Germany.
authors.forename: Veit
authors.initials: V
authors.lastname: Althoff
authors.affiliation: Tanz Centre for Research in Neurodegenerative Diseases, Departments of Medicine and Medical Biophysics, University of Toronto, Toronto, ON, Canada.
authors.forename: Paul E
authors.initials: PE
authors.lastname: Fraser
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
authors.forename: Lili-Naz
authors.initials: LN
authors.lastname: Hazrati
authors.affiliation: Tanz Centre for Research in Neurodegenerative Diseases, Departments of Medicine and Medical Biophysics, University of Toronto, Toronto, ON, Canada.
authors.forename: Peter St
authors.initials: PS
authors.lastname: George-Hyslop
authors.affiliation: Douglas Mental Health University Institute, Verdun, QC, Canada Department of Psychiatry, McGill University Faculty of Medicine, Montreal, QC, Canada.
authors.forename: John C S
authors.initials: JC
authors.lastname: Breitner
authors.affiliation: Department of Psychiatry and Psychotherapy, Campus Benjamin Franklin, Charite-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Peters
authors.affiliation: Institut fuer Chemie und Biochemie, Freie Universitaet Berlin, Berlin, Germany Department of Pharmacology & Therapeutics, McGill University, Montreal, QC, Canada.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Multhaup
mesh_terms: D000544:Alzheimer Disease / Q000134:cerebrospinal fluid; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D002540:Cerebral Cortex / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D006624:Hippocampus / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000378:metabolism; D018975:Insulin-Like Growth Factor Binding Protein 5 / Q000378:metabolism; D008822:Mice, Transgenic; D046228:Microarray Analysis; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D011569:Psychiatric Status Rating Scales; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D016229:Amyloid beta-Peptides; C515497:IGFBP3 protein, human; D018972:Insulin-Like Growth Factor Binding Protein 3; D018975:Insulin-Like Growth Factor Binding Protein 5; D010446:Peptide Fragments; D012333:RNA, Messenger; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)
keywords: Alzheimer's disease; CSF proteomics; ID1-3; IGFBP; LMO4; amyloid-β; gene regulation; immunohistochemistry; transcription factors