title: The amyloid precursor protein represses expression of acetylcholinesterase in neuronal cell lines.
abstract: The toxic role of amyloid β peptides in Alzheimer's disease is well documented. Their generation is via sequential β- and γ-secretase cleavage of the membrane-bound amyloid precursor protein (APP). Other APP metabolites include the soluble ectodomains sAPPα and sAPPβ and also the amyloid precursor protein intracellular domain (AICD). In this study, we examined whether APP is involved in the regulation of acetylcholinesterase (AChE), which is a key protein of the cholinergic system and has been shown to accelerate amyloid fibril formation and increase their toxicity. Overexpression of the neuronal specific isoform, APP695, in the neuronal cell lines SN56 and SH-SY5Y substantially decreased levels of AChE mRNA, protein, and catalytic activity. Although similar decreases in mRNA levels were observed of the proline-rich anchor of AChE, PRiMA, no changes were seen in mRNA levels of the related enzyme, butyryl-cholinesterase, nor of the high-affinity choline transporter. A γ-secretase inhibitor did not affect AChE transcript levels or enzyme activity in SN56 (APP695) or SH-SY5Y (APP695) cells, showing that regulation of AChE by APP does not require the generation of AICD or amyloid β peptide. Treatment of wild-type SN56 cells with siRNA targeting APP resulted in a significant up-regulation in AChE mRNA levels. Mutagenesis studies suggest that the observed transcriptional repression of AChE is mediated by the E1 region of APP, specifically its copper-binding domain, but not the C-terminal YENTPY motif. In conclusion, AChE is regulated in two neuronal cell lines by APP in a manner independent of the generation of sAPPα, sAPPβ, and AICD.
authors.affiliation: From the School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, United Kingdom.
authors.forename: David A
authors.initials: DA
authors.lastname: Hicks
authors.affiliation: From the School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, United Kingdom.
authors.forename: Natalia Z
authors.initials: NZ
authors.lastname: Makova
authors.affiliation: the Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancaster LA1 4YQ, United Kingdom, and.
authors.forename: Mallory
authors.initials: M
authors.lastname: Gough
authors.affiliation: the Division of Biomedical and Life Sciences, Faculty of Health and Medicine, Lancaster University, Lancaster LA1 4YQ, United Kingdom, and.
authors.forename: Edward T
authors.initials: ET
authors.lastname: Parkin
authors.affiliation: From the School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, United Kingdom,; the I.M. Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, St. Petersburg 194223, Russia.
authors.forename: Natalia N
authors.initials: NN
authors.lastname: Nalivaeva
authors.affiliation: From the School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, United Kingdom,. Electronic address: a.j.turner@leeds.ac.uk.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Turner
mesh_terms: D000110:Acetylcholinesterase / Q000235:genetics / Q000378:metabolism*; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020816:Amino Acid Motifs; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D058851:GPI-Linked Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D058851:GPI-Linked Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C446290:PRIMA1 protein, human; D012333:RNA, Messenger; C486718:prima1 protein, mouse; C548244:ACHE protein, human; D000110:Acetylcholinesterase; C548245:Ache protein, mouse
keywords: AICD; Acetylcholinesterase; Alzheimer's Disease; Amyloid Precursor Protein; Cell Culture; Transfection; γ-Secretase Inhibitor
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