Blockade of tau hyperphosphorylation and aβ 1-42 generation by the aminotetrahydrofuran derivative ANAVEX2-73, a mixed muscarinic and σ 1 receptor agonist, in a nontransgenic mouse model of Alzheimer's disease

Valentine Lahmy, Johann Meunier, Susanna Malmström, Gaelle Naert, Laurent Givalois, Seung Hyun Kim, Vanessa Villard, Alexandre Vamvakides, Tangui Maurice

Research output: Contribution to journalArticle

75 Scopus citations

Abstract

The main objective of the present study was to establish whether the mixed σ 1/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 Aβ 25-35 mouse model of AD. We therefore first confirmed that Aβ 25-35 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 Aβ 25-35-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 Aβ 25-35-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 σ 1 receptor agonist, and xanomeline, a muscarinic ligand presenting similar profile as ANAVEX2-73 on M1 and M2 subtypes, confirmed that both muscarinic and σ 1 targets are involved in the ANAVEX2-73 effects. The drug, acting synergistically on both targets, but with moderate affinity, presents a promising pharmacological profile.

Original languageEnglish
Pages (from-to)1706-1723
Number of pages18
JournalNeuropsychopharmacology
Volume38
Issue number9
DOIs
StatePublished - 2013 Aug 1

Keywords

  • Alzheimer's disease
  • GSK-3b inhibitor
  • Tau hyperphosphorylation
  • amyloid toxicity
  • muscarinic ligand
  • α1 receptor

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