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Peripheral and Central Effects of Memantine in a Mixed Preclinical Mice Model of Obesity and Familial Alzheimer’s Disease

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A Correction to this article was published on 04 May 2020

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Abstract

There is growing evidence that obesity associated with type 2 diabetes mellitus (T2DM) and aging are risk factors for the development of Alzheimer’s disease (AD). However, the molecular mechanisms through which obesity interacts with β-amyloid (Aβ) to promote cognitive decline remains poorly understood. Memantine (MEM), a N-methyl-d-aspartate receptor antagonist, is currently used for the treatment of AD. Nonetheless, few studies have reported its effects on genetic preclinical models of this neurodegenerative disease exacerbated with high-fat diet (HFD)-induced obesity. Therefore, the present research aims to elucidate the effects of MEM on familial AD HFD-induced insulin resistance and learning and memory impairment. Furthermore, it aspires to determine the possible underlying mechanisms that connect AD to T2DM. Wild type and APPswe/PS1dE9 mice were used in this study. The animals were fed with either chow or HFD until 6 months of age, and they were treated with MEM-supplemented water (30 mg/kg) during the last 12 weeks. Our study demonstrates that MEM improves the metabolic consequences produced by HFD in this model of familial AD. Behavioural assessments confirmed that the treatment also improves animals learning abilities and decreases memory loss. Moreover, MEM treatment improves brain insulin signalling upregulating AKT, as well as cyclic adenosine monophosphate response element binding (CREB) expression, and modulates the amyloidogenic pathway, which, in turn, reduced the accumulation of Aβ. Moreover, this drug increases the activation of molecules involved with insulin signalling in the liver, such as insulin receptor substrate 2 (IRS2), which is a key protein regulating hepatic resistance to insulin. These results provide new insight into the role of MEM not only in the occurrence of AD treatment, but also in its potential application on peripheral metabolic disorders where Aβ plays a key role, as is the case of T2DM.

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  • 04 May 2020

    The original version of this article unfortunately contained mistake. The authors found that Fig.��4.B mistakenly displays an incorrect GAPDH image. The authors are truly regretful and apologize for the mistake.

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Acknowledgements

Henry Cabrera , acknowledges the research fellowship from Senescyt (Ecuador).

Funding

This work was supported by the Spanish Ministry of Science and Innovation SAF2017-84283-R to AC, SAF2015-64146-R to MVC, PI2016/01, CB06/05/0024 (CIBERNED), CB07/08/003 (CIBERDEM), the European Regional Development Founds and the MAT 2014-59134-R project. Research team from UB and URV belongs to 2014SGR-525 from Generalitat de Catalunya. ESL and MLG belong to 2014SGR-1023 and the second author, ESL, acknowledges the Ph.D. scholarship FPI-MICINN (BES-2012-026083). GC acknowledges The National Institutes of Health (1R15AG050292-01A1).

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Authors and Affiliations

  1. Departament de Farmacología, Toxicologia i Quimica Terapéutica, Unitat de Farmacologia i Farmacognosia, Facultat de Farmacia i Ciències de l’Alimentació, Universitat de Barcelona, Av. Joan XXIII s/n, 08028, Barcelona, Spain

    Miren Ettcheto, Yaiza Gómez-Mínguez, Henrry Cabrera, Oriol Busquets, Manuel Vázquez Carrera & Antoni Camins

  2. Biomedical Research Networking Center in Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain

    Miren Ettcheto, Elena Sánchez-López, Oriol Busquets, Jaume Folch & Antoni Camins

  3. Unitat de Bioquímica i Biotecnologia, Facultat de Medicina i Ciències de la Salut, Universitat Rovira i Virgili, Reus, Tarragona, Spain

    Miren Ettcheto, Oriol Busquets & Jaume Folch

  4. Institut de Neurociencias, Universitat de Barcelona, Barcelona, Spain

    Miren Ettcheto, Oriol Busquets & Antoni Camins

  5. Unitat de Farmacia, Tecnologia Farmacèutica i Fisico-química, Facultat de Farmàcia i Ciències de l’Alimentació, Universitat de Barcelona, Barcelona, Spain

    Elena Sánchez-López & Maria Luisa García

  6. Institute of Nanoscience and Nanotechnology (IN2UB), University of Barcelona, Barcelona, Spain

    Elena Sánchez-López & Maria Luisa García

  7. Departamento de Biología Celular y Molecular, C.U.C.B.A, Universidad de Guadalajara and División de Neurociencias, Sierra Mojada 800, Col. Independencia, 44340, Guadalajara, Jalisco, Mexico

    Carlos Beas-Zarate

  8. Neurodegenerative Disorders Group, Instituto de Investigacion Hospital 12 de Octubre (i + 12), Madrid, Spain

    Eva Carro

  9. Department of Biological Sciences, Kent State University, Kent, OH, USA

    Gemma Casadesus

  10. Departament de Biologia Cel·lular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain

    Carme Auladell

  11. Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona, Spain

    Manuel Vázquez Carrera

  12. Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Barcelona, Spain

    Manuel Vázquez Carrera

  13. Research Institute-Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain

    Manuel Vázquez Carrera

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  1. Miren Ettcheto
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  2. Elena Sánchez-López
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All the authors had directly participated on the execution and planning of the manuscript.

Corresponding author

Correspondence to Antoni Camins.

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Mice were treated in accordance with the European Community Council Directive 86/609/EEC and the procedures established by the Department d’Agricultura, Ramaderia i Pesca of the Generalitat de Catalunya.

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The authors declare that there is no conflict of interest.

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Jaume Folch and Antoni Camins are senior co-authors.

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Ettcheto, M., Sánchez-López, E., Gómez-Mínguez, Y. et al. Peripheral and Central Effects of Memantine in a Mixed Preclinical Mice Model of Obesity and Familial Alzheimer’s Disease. Mol Neurobiol 55, 7327–7339 (2018). https://doi.org/10.1007/s12035-018-0868-4

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