Tetracyclic Truncated Analogue of the Marine Toxin Gambierol Modifies NMDA, Tau, and Amyloid β Expression in Mice Brains: Implications in AD Pathology

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...

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Published in:ACS chemical neuroscience 2017-06, Vol.8 (6), p.1358-1367
Main Authors: Alonso, Eva, Vieira, Andrés C, Rodriguez, Inés, Alvariño, Rebeca, Gegunde, Sandra, Fuwa, Haruhiko, Suga, Yuto, Sasaki, Makoto, Alfonso, Amparo, Cifuentes, José Manuel, Botana, Luis M
Format: Article
Language:English
Subjects:
Alzheimer Disease - metabolism
Alzheimer Disease - pathology
Amyloid beta-Peptides - drug effects
Animals
Brain - drug effects
Brain - metabolism
Brain - pathology
Ciguatoxins - pharmacology
Mice
Mice, Transgenic
Phosphorylation
Receptors, N-Methyl-D-Aspartate - drug effects
tau Proteins - drug effects
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Summary: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 β1–42 levels 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 β1–42 and 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.
ISSN:1948-7193
1948-7193
DOI:10.1021/acschemneuro.7b00012