title: Blockade of Tau hyperphosphorylation and Aβ₁₋₄₂ generation by the aminotetrahydrofuran derivative ANAVEX2-73, a mixed muscarinic and σ₁ receptor agonist, in a nontransgenic mouse model of Alzheimer's disease.
abstract: The main objective of the present study was to establish whether the mixed σ₁/muscarinic ligand ANAVEX2-73, shown to be neuroprotective in Alzheimer's disease (AD) models in vivo and currently in clinical phase I/IIa, could have the ability to reduce the appearance of hyperphosphorylated Tau and amyloid-β₁₋₄₂ (Aβ₁₋₄₂ in the Aβ₂₅₋₃₅ mouse model of AD. We therefore first confirmed that Aβ₂₅₋₃₅ injection induced hyperphosphorylation of Tau protein, by showing that it rapidly decreased Akt activity and activated glycogen synthase kinase-3β (GSK-3β) in the mouse hippocampus. Second, we showed that the kinase activation, and resulting Tau alteration, directly contributed to the amyloid toxicity, as co-administration of the selective GSK-3β inhibitor 2-thio(3-iodobenzyl)-5-(1-pyridyl)-[1,3,4]-oxidiazole blocked both Tau phosphorylation and Aβ₂₅₋₃₅-induced memory impairments. Third, we analyzed the ANAVEX2-73 effect on Tau phosphorylation and activation of the related kinase pathways (Akt and GSK-3β). And fourth, we also addressed the impact of the drug on Aβ₂₅₋₃₅-induced Aβ₁₋₄₂ seeding and observed that the compound significantly blocked the increase in Aβ₁₋₄₂ and C99 levels in the hippocampus, suggesting that it may alleviate amyloid load in AD models. The comparison with PRE-084, a selective and reference σ₁ receptor agonist, and xanomeline, a muscarinic ligand presenting similar profile as ANAVEX2-73 on M1 and M2 subtypes, confirmed that both muscarinic and σ₁ targets are involved in the ANAVEX2-73 effects. The drug, acting synergistically on both targets, but with moderate affinity, presents a promising pharmacological profile.
authors.affiliation: INSERM U710, Montpellier, France.
authors.forename: Valentine
authors.initials: V
authors.lastname: Lahmy
authors.forename: Johann
authors.initials: J
authors.lastname: Meunier
authors.forename: Susanna
authors.initials: S
authors.lastname: Malmström
authors.forename: Gaelle
authors.initials: G
authors.lastname: Naert
authors.forename: Laurent
authors.initials: L
authors.lastname: Givalois
authors.forename: Seung Hyun
authors.initials: SH
authors.lastname: Kim
authors.forename: Vanessa
authors.initials: V
authors.lastname: Villard
authors.forename: Alexandre
authors.initials: A
authors.lastname: Vamvakides
authors.forename: Tangui
authors.initials: T
authors.lastname: Maurice
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000008:administration & dosage / Q000096:biosynthesis* / Q000633:toxicity; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005663:Furans / Q000494:pharmacology* / Q000627:therapeutic use; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D057967:Infusions, Intraventricular; D008297:Male; D008569:Memory Disorders / Q000139:chemically induced / Q000188:drug therapy; D051379:Mice; D009025:Morpholines / Q000494:pharmacology / Q000627:therapeutic use; D018721:Muscarinic Agonists / Q000494:pharmacology* / Q000627:therapeutic use; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D010069:Oxadiazoles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D010446:Peptide Fragments / Q000008:administration & dosage / Q000096:biosynthesis* / Q000378:metabolism / Q000633:toxicity; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D017480:Receptors, sigma / Q000819:agonists*; D015398:Signal Transduction / Q000187:drug effects; D013830:Thiadiazoles / Q000494:pharmacology / Q000627:therapeutic use; D016875:tau Proteins / Q000378:metabolism*
chemical_list: C529548:2-thio(3-iodobenzyl)-5-(1-pyridyl)-(1,3,4)oxadiazole; D016229:Amyloid beta-Peptides; D005663:Furans; C558298:Mapt protein, mouse; D009025:Morpholines; D018721:Muscarinic Agonists; D018696:Neuroprotective Agents; D010069:Oxadiazoles; D010446:Peptide Fragments; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D017480:Receptors, sigma; D013830:Thiadiazoles; C075222:amyloid beta-protein (1-42); C074636:amyloid beta-protein (25-35); D016875:tau Proteins; C568535:tetrahydro-N, N-dimethyl-2,2-diphenyl-3-furanmethanamine hydrochloride; C071738:2-(4-morpholino)ethyl-1-phenylcyclohexane-1-carboxylate; C075257:xanomeline; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3