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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

Title
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
Author
김승현
Keywords
sigma(1) receptor; muscarinic ligand; amyloid toxicity; GSK-3 beta inhibitor; Tau hyperphosphorylation; Alzheimer's disease
Issue Date
2013-08
Publisher
NATURE PUBLISHING GROUP
Citation
NEUROPSYCHOPHARMACOLOGY, Aug 2013,38(9), P.1706-1723
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.
URI
https://www.nature.com/articles/npp201370http://hdl.handle.net/20.500.11754/50047
ISSN
1740-634X
DOI
10.1038/npp.2013.70
Appears in Collections:
COLLEGE OF MEDICINE[S](의과대학) > ETC
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