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

被引：14

作者：

Alonso, Eva ^{[1
]}

Vieira, Andres C. ^{[1
]}

Rodriguez, Ines ^{[1
]}

Alvarino, Rebeca ^{[1
]}

Gegunde, Sandra ^{[1
]}

Fuwa, Haruhiko ^{[3
]}

Suga, Yuto ^{[3
]}

Sasaki, Makoto ^{[3
]}

Alfonso, Amparo ^{[1
]}

Manuel Cifuentes, Jose ^{[2
]}

Botana, Luis M. ^{[1
]}

机构：

[1] Univ Santiago de Compostela, Fac Vet, Dept Farmacol, Lugo 27002, Spain

[2] Univ Santiago de Compostela, Fac Vet, Dept Anat, Lugo 27002, Spain

[3] Tohoku Univ, Grad Sch Life Sci, Aoba Ku, 2-1-1 Katahira, Sendai, Miyagi 9808577, Japan

来源：

ACS CHEMICAL NEUROSCIENCE | 2017年 / 8卷 / 06期

基金：

日本科学技术振兴机构;

关键词：

Gambierol; Gambierdiscus; Alzheimer's; NMDA receptor; tau; beta-amyloid; DINOFLAGELLATE GAMBIERDISCUS-TOXICUS; GATED POTASSIUM CHANNELS; TRIPLE-TRANSGENIC MODEL; ALZHEIMERS-DISEASE; BIOLOGICAL EVALUATION; INHIBITION; CURRENTS; K+; RECEPTOR; NEURONS;

D O I：

10.1021/acschemneuro.7b00012

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 mu g/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 beta(1-42) levels and a dose-dependent inhibition of beta-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-3 beta. 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 beta(1-42) 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.

引用

页码：1358 / 1367

页数：10

共 37 条

[1] Design and Synthesis of Skeletal Analogues of Gambierol: Attenuation of Amyloid-β and Tau Pathology with Voltage-Gated Potassium Channel and N-Methyl-D-aspartate Receptor Implications [J].