Blockade of Tau Hyperphosphorylation and A beta(1-42) Generation by the Aminotetrahydrofuran Derivative ANAVEX2-73, a Mixed Muscarinic and sigma(1) Receptor Agonist, in a Nontransgenic Mouse Model of Alzheimer's Disease
- Authors
- Lahmy, Valentine; Meunier, Johann; Malmstroem, Susanna; Naert, Gaelle; Givalois, Laurent; Kim, Seung Hyun; Villard, Vanessa; Vamvakides, Alexandre; Maurice, Tangui
- Issue Date
- Aug-2013
- Publisher
- NATURE PUBLISHING GROUP
- Keywords
- sigma(1) receptor; muscarinic ligand; amyloid toxicity; GSK-3 beta inhibitor; Tau hyperphosphorylation; Alzheimer' s disease
- Citation
- NEUROPSYCHOPHARMACOLOGY, v.38, no.9, pp.1706 - 1723
- Indexed
- SCIE
SCOPUS
- Journal Title
- NEUROPSYCHOPHARMACOLOGY
- Volume
- 38
- Number
- 9
- Start Page
- 1706
- End Page
- 1723
- URI
- https://scholarworks.bwise.kr/hanyang/handle/2021.sw.hanyang/162242
- DOI
- 10.1038/npp.2013.70
- ISSN
- 0893-133X
- Abstract
- The main objective of the present study was to establish whether the mixed sigma(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-beta(1-42) (A beta(1-42)) in the A beta(25-35) mouse model of AD. We therefore first confirmed that A beta(25-35) injection induced hyperphosphorylation of Tau protein, by showing that it rapidly decreased Akt activity and activated glycogen synthase kinase-3 beta (GSK-3 beta) 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-3 beta inhibitor 2-thio(3-iodobenzyl)-5-(1-pyridyl)-[1,3,4]-oxidiazole blocked both Tau phosphorylation and A beta(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-3b). And fourth, we also addressed the impact of the drug on A beta(25-35)-induced A beta(1-42) seeding and observed that the compound significantly blocked the increase in A beta(1-42) 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 sigma(1) receptor agonist, and xanomeline, a muscarinic ligand presenting similar profile as ANAVEX2-73 on M1 and M2 subtypes, confirmed that both muscarinic and s1 targets are involved in the ANAVEX2-73 effects. The drug, acting synergistically on both targets, but with moderate affinity, presents a promising pharmacological profile.
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