title: Amyloid precursor-like protein 1 (APLP1) exhibits stronger zinc-dependent neuronal adhesion than amyloid precursor protein and APLP2.
abstract: The amyloid precursor protein (APP) and its paralogs, amyloid precursor-like protein 1 (APLP1) and APLP2, are metalloproteins with a putative role both in synaptogenesis and in maintaining synapse structure. Here, we studied the effect of zinc on membrane localization, adhesion, and secretase cleavage of APP, APLP1, and APLP2 in cell culture and rat neurons. For this, we employed live-cell microscopy techniques, a microcontact printing adhesion assay and ELISA for protein detection in cell culture supernatants. We report that zinc induces the multimerization of proteins of the amyloid precursor protein family and enriches them at cellular adhesion sites. Thus, zinc facilitates the formation of de novo APP and APLP1 containing adhesion complexes, whereas it does not have such influence on APLP2. Furthermore, zinc-binding prevented cleavage of APP and APLPs by extracellular secretases. In conclusion, the complexation of zinc modulates neuronal functions of APP and APLPs by (i) regulating formation of adhesion complexes, most prominently for APLP1, and (ii) by reducing the concentrations of neurotrophic soluble APP/APLP ectodomains. Earlier studies suggest a function of the amyloid precursor protein (APP) family proteins in neuronal adhesion. We report here that adhesive function of these proteins is tightly regulated by zinc, most prominently for amyloid precursor-like protein 1 (APLP1). Zinc-mediated APLP1 multimerization, which induced formation of new neuronal contacts and decreased APLP1 shedding. This suggests that APLP1 could function as a zinc receptor processing zinc signals to stabilized or new neuronal contacts.
authors.affiliation: Institut für Chemie und Biochemie, Freie Universität Berlin, Berlin, Germany.
authors.forename: Magnus C
authors.initials: MC
authors.lastname: Mayer
authors.affiliation: Institut für Chemie und Biochemie, Freie Universität Berlin, Berlin, Germany.
authors.forename: Linda
authors.initials: L
authors.lastname: Schauenburg
authors.affiliation: McGill Program in Neuroengineering, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.
authors.forename: Greta
authors.initials: G
authors.lastname: Thompson-Steckel
authors.affiliation: Institut für Biologie, Humboldt-Universität zu Berlin, Berlin, Germany.
authors.forename: Valentin
authors.initials: V
authors.lastname: Dunsing
authors.affiliation: Institut für Chemie und Biochemie, Freie Universität Berlin, Berlin, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Kaden
authors.affiliation: Molekulare Pharmakologie und Zellbiologie, Neurowissenschaftliches Forschungszentrum, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Voigt
authors.affiliation: Medizinische Fakultät der Universität Leipzig, Rudolf-Boehm-Institut für Pharmakologie und Toxikologie, Leipzig, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Schaefer
authors.affiliation: Institut für Biochemie und Biologie, Universität Potsdam, Potsdam, Germany.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Chiantia
authors.affiliation: McGill Program in Neuroengineering, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Quebec, Canada.
authors.forename: Timothy E
authors.initials: TE
authors.lastname: Kennedy
authors.affiliation: Institut für Chemie und Biochemie, Freie Universität Berlin, Berlin, Germany.|Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Multhaup
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004622:Embryo, Mammalian; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D038761:Photobleaching; D051381:Rats; D017207:Rats, Sprague-Dawley; D014162:Transfection; D015032:Zinc / Q000494:pharmacology*
chemical_list: C489697:APLP1 protein, human; C084104:APLP2 protein, human; D016564:Amyloid beta-Protein Precursor; D001426:Bacterial Proteins; D008164:Luminescent Proteins; D009419:Nerve Tissue Proteins; C054562:yellow fluorescent protein, Bacteria; D015032:Zinc
keywords: amyloid precursor protein; amyloid precursor-like protein; neuronal adhesion; number and brightness; zinc