title: Lynx1 and Aβ1-42 bind competitively to multiple nicotinic acetylcholine receptor subtypes.
abstract: Lynx1 regulates synaptic plasticity in the brain by regulating nicotinic acetylcholine receptors (nAChRs). It is not known to which extent Lynx1 can bind to endogenous nAChR subunits in the brain or how this interaction is affected by Alzheimer's disease pathology. We apply affinity purification to demonstrate that a water-soluble variant of human Lynx1 (Ws-Lynx1) isolates α3, α4, α5, α6, α7, β2, and β4 nAChR subunits from human and rat cortical extracts, and rat midbrain and olfactory bulb extracts, suggesting that Lynx1 forms complexes with multiple nAChR subtypes in the human and rodent brain. Incubation with Ws-Lynx1 decreases nicotine-mediated extracellular signal-regulated kinase phosphorylation in PC12 cells and striatal neurons, indicating that binding of Ws-Lynx1 is sufficient to inhibit signaling downstream of nAChRs. The effect of nicotine in PC12 cells is independent of α7 or α4β2 nAChRs, suggesting that Lynx1 can affect the function of native non-α7, non-α4β2 nAChR subtypes. We further show that Lynx1 and oligomeric β-amyloid1-42 compete for binding to several nAChR subunits, that Ws-Lynx1 prevents β-amyloid1-42-induced cytotoxicity in cortical neurons, and that cortical Lynx1 levels are decreased in a transgenic mouse model with concomitant β-amyloid and tau pathology. Our data suggest that Lynx1 binds to multiple nAChR subtypes in the brain and that this interaction might have functional and pathophysiological implications in relation to Alzheimer's disease.
authors.affiliation: Neurobiology Research Unit, University Hospital Copenhagen, Rigshospitalet, Copenhagen, Denmark; Department of Drug Design & Pharmacology, University of Copenhagen, Copenhagen, Denmark. Electronic address: morten.s.thomsen@sund.ku.dk.
authors.forename: Morten S
authors.initials: MS
authors.lastname: Thomsen
authors.affiliation: Department of Drug Design & Pharmacology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Maria
authors.initials: M
authors.lastname: Arvaniti
authors.affiliation: Neurobiology Research Unit, University Hospital Copenhagen, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Majbrit M
authors.initials: MM
authors.lastname: Jensen
authors.affiliation: Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia; Lomonosov Moscow State University, Moscow, Russia.
authors.forename: Mikhail A
authors.initials: MA
authors.lastname: Shulepko
authors.affiliation: Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia; Lomonosov Moscow State University, Moscow, Russia.
authors.forename: Dmitry A
authors.initials: DA
authors.lastname: Dolgikh
authors.affiliation: Neurobiology Research Unit, University Hospital Copenhagen, Rigshospitalet, Copenhagen, Denmark; Epilepsy Clinic, University Hospital Copenhagen, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Lars H
authors.initials: LH
authors.lastname: Pinborg
authors.affiliation: Paul Flechsig Institute for Brain Research, University of Leipzig, Leipzig, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Härtig
authors.affiliation: Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia; Lomonosov Moscow State University, Moscow, Russia.
authors.forename: Ekaterina N
authors.initials: EN
authors.lastname: Lyukmanova
authors.affiliation: Neurobiology Research Unit, University Hospital Copenhagen, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Jens D
authors.initials: JD
authors.lastname: Mikkelsen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000494:Allosteric Regulation; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000502:physiology; D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D004195:Disease Models, Animal; D058851:GPI-Linked Proteins / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D008822:Mice, Transgenic; D016716:PC12 Cells; D010446:Peptide Fragments / Q000378:metabolism* / Q000502:physiology; D011485:Protein Binding; D051381:Rats; D011978:Receptors, Nicotinic / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D024801:Tauopathies / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016229:Amyloid beta-Peptides; D058851:GPI-Linked Proteins; C485626:LYNX1 protein, human; D010446:Peptide Fragments; D011978:Receptors, Nicotinic; C075222:amyloid beta-protein (1-42)
keywords: Allosteric modulator; Alzheimer's disease; Ly-6; Lynx; nAChR