title: Nicotine prevents synaptic impairment induced by amyloid-β oligomers through α7-nicotinic acetylcholine receptor activation.
abstract: An emerging view on Alzheimer disease's (AD) pathogenesis considers amyloid-β (Aβ) oligomers as a key factor in synaptic impairment and rodent spatial memory decline. Alterations in the α7-nicotinic acetylcholine receptor (α7-nAChR) have been implicated in AD pathology. Herein, we report that nicotine, an unselective α7-nAChR agonist, protects from morphological and synaptic impairments induced by Aβ oligomers. Interestingly, nicotine prevents both early postsynaptic impairment and late presynaptic damage induced by Aβ oligomers through the α7-nAChR/phosphatidylinositol-3-kinase (PI3K) signaling pathway. On the other hand, a cross-talk between α7-nAChR and the Wnt/β-catenin signaling pathway was revealed by the following facts: (1) nicotine stabilizes β-catenin, in a concentration-dependent manner; (2) nicotine prevents Aβ-induced loss of β-catenin through the α7-nAChR; and (3) activation of canonical Wnt/β-catenin signaling induces α7-nAChR expression. Analysis of the α7-nAChR promoter indicates that this receptor is a new Wnt target gene. Taken together, these results demonstrate that nicotine prevents memory deficits and synaptic impairment induced by Aβ oligomers. In addition, nicotine improves memory in young APP/PS1 transgenic mice before extensive amyloid deposition and senile plaque development, and also in old mice where senile plaques have already formed. Activation of the α7-nAChR/PI3K signaling pathway and its cross-talk with the Wnt signaling pathway might well be therapeutic targets for potential AD treatments.
authors.affiliation: Centro de Envejecimiento y Regeneración (CARE), Pontificia Universidad Católica de Chile, PO Box 114-D, Santiago, Chile. ninestrosa@bio.puc.cl
authors.forename: Nibaldo C
authors.initials: NC
authors.lastname: Inestrosa
authors.forename: Juan A
authors.initials: JA
authors.lastname: Godoy
authors.forename: Jessica Y
authors.initials: JY
authors.lastname: Vargas
authors.forename: Macarena S
authors.initials: MS
authors.lastname: Arrazola
authors.forename: Juvenal A
authors.initials: JA
authors.lastname: Rios
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Carvajal
authors.forename: Felipe G
authors.initials: FG
authors.lastname: Serrano
authors.forename: Ginny G
authors.initials: GG
authors.lastname: Farias
mesh_terms: D000544:Alzheimer Disease / Q000517:prevention & control*; D016229:Amyloid beta-Peptides / Q000138:chemical synthesis / Q000633:toxicity*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D002038:Bungarotoxins / Q000494:pharmacology; D002478:Cells, Cultured; D003712:Dendrites / Q000187:drug effects / Q000648:ultrastructure; D000076122:Disks Large Homolog 4 Protein; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000032:analysis; D018782:Maze Learning / Q000187:drug effects; D008565:Membrane Proteins / Q000032:analysis; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016501:Neurites / Q000648:ultrastructure; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D009538:Nicotine / Q000494:pharmacology* / Q000627:therapeutic use; D018408:Patch-Clamp Techniques; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000633:toxicity*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D058225:Plaque, Amyloid / Q000378:metabolism; D053764:Presenilin-1 / Q000235:genetics; D017729:Presynaptic Terminals / Q000187:drug effects / Q000648:ultrastructure; D051381:Rats; D017207:Rats, Sprague-Dawley; D011993:Recombinant Fusion Proteins / Q000235:genetics; D015398:Signal Transduction; D016704:Synapsins / Q000032:analysis; D051153:Wnt Proteins / Q000502:physiology; D060449:Wnt Signaling Pathway; D000077191:Wortmannin; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000819:agonists / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D051176:beta Catenin / Q000502:physiology
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000730:Androstadienes; D002038:Bungarotoxins; C495267:CTNNB1 protein, mouse; C579166:Chrna7 protein, mouse; C579165:Chrna7 protein, rat; C495268:Ctnnb1 protein, rat; D000076122:Disks Large Homolog 4 Protein; C501449:Dlg4 protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; D011993:Recombinant Fusion Proteins; D016704:Synapsins; D051153:Wnt Proteins; D064569:alpha7 Nicotinic Acetylcholine Receptor; C075222:amyloid beta-protein (1-42); D051176:beta Catenin; D009538:Nicotine; D019869:Phosphatidylinositol 3-Kinases; D000077191:Wortmannin