title: Tetracyclic Truncated Analogue of the Marine Toxin Gambierol Modifies NMDA, Tau, and Amyloid β Expression in Mice Brains: Implications in AD Pathology.
abstract: Gambierol and its two, tetra- and heptacyclic, analogues have been previously proved as promising molecules for the modulation of Alzheimer's disease (AD) hallmarks in primary cortical neurons of 3xTg-AD fetuses. In this work, the effect of the tetracyclic analogue of gambierol was tested in vivo in 3xTg-AD mice (10 months old) after 1 month of weekly treatment with 50 μg/kg. Adverse effects were not reported throughout the whole treatment period and no pathological signs were observed for the analyzed organs. The compound was found in brain samples after intraperitoneal injection. The tetracyclic analogue of gambierol elicited a decrease of amyloid β1-42levels and a dose-dependent inhibition of β-secretase enzyme-1 activity. Moreover, this compound also reduced the phosphorylation of tau at the 181 and 159/163 residues with an increase of the inactive isoform of the glycogen synthase kinase-3β. In accordance with our in vitro neuronal model, this compound produced a reduction in the N2A subunit of the N-methyl-d-aspartate (NMDA) receptor. The combined effect of this compound on amyloid β1-42and tau phosphorylation represents a multitarget therapeutic approach for AD which might be more effective for this multifactorial and complex neurodegenerative disease than the current treatments.
authors.affiliation: Departamento de Farmacología, §Departamento de Anatomía, Facultad de Veterinaria, Universidad de Santiago de Compostela , 27002 Lugo, Spain.
authors.forename: Eva
authors.identifier: 0000-0002-1131-6575
authors.initials: E
authors.lastname: Alonso
authors.affiliation: Departamento de Farmacología, §Departamento de Anatomía, Facultad de Veterinaria, Universidad de Santiago de Compostela , 27002 Lugo, Spain.
authors.forename: Andrés C
authors.initials: AC
authors.lastname: Vieira
authors.affiliation: Departamento de Farmacología, §Departamento de Anatomía, Facultad de Veterinaria, Universidad de Santiago de Compostela , 27002 Lugo, Spain.
authors.forename: Inés
authors.initials: I
authors.lastname: Rodriguez
authors.affiliation: Departamento de Farmacología, §Departamento de Anatomía, Facultad de Veterinaria, Universidad de Santiago de Compostela , 27002 Lugo, Spain.
authors.forename: Rebeca
authors.initials: R
authors.lastname: Alvariño
authors.affiliation: Departamento de Farmacología, §Departamento de Anatomía, Facultad de Veterinaria, Universidad de Santiago de Compostela , 27002 Lugo, Spain.
authors.forename: Sandra
authors.initials: S
authors.lastname: Gegunde
authors.affiliation: Graduate School of Life Sciences, Tohoku University , 2-1-1 Katahira, Aoba-ku, Sendai 980-8577, Japan.
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Fuwa
authors.affiliation: Graduate School of Life Sciences, Tohoku University , 2-1-1 Katahira, Aoba-ku, Sendai 980-8577, Japan.
authors.forename: Yuto
authors.initials: Y
authors.lastname: Suga
authors.affiliation: Graduate School of Life Sciences, Tohoku University , 2-1-1 Katahira, Aoba-ku, Sendai 980-8577, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Sasaki
authors.affiliation: Departamento de Farmacología, §Departamento de Anatomía, Facultad de Veterinaria, Universidad de Santiago de Compostela , 27002 Lugo, Spain.
authors.forename: Amparo
authors.initials: A
authors.lastname: Alfonso
authors.forename: José Manuel
authors.initials: JM
authors.lastname: Cifuentes
authors.affiliation: Departamento de Farmacología, §Departamento de Anatomía, Facultad de Veterinaria, Universidad de Santiago de Compostela , 27002 Lugo, Spain.
authors.forename: Luis M
authors.initials: LM
authors.lastname: Botana
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000187:drug effects*; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002922:Ciguatoxins / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D010766:Phosphorylation; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects*; D016875:tau Proteins / Q000187:drug effects*; D035964:Oxocins
chemical_list: D016229:Amyloid beta-Peptides; D002922:Ciguatoxins; D016194:Receptors, N-Methyl-D-Aspartate; D016875:tau Proteins; C435770:gambierol; D035964:Oxocins
keywords: Alzheimer’s; Gambierdiscus; Gambierol; NMDA receptor; tau; β-amyloid