Peripheral and Central Effects of Memantine in a Mixed Preclinical Mice Model of Obesity and Familial Alzheimer’s Disease
Authors: Yaiza Gómez-Mínguez
Manuel Vázquez Carrera
Henrry Cabrera
Maria Luisa García
Eva Carro
Miren Ettcheto
Carme Auladell
Elena Sánchez-López
Carlos Beas-Zarate
Antoni Camins
Gemma Casadesus
Oriol Busquets
Jaume Folch
Journal: Molecular Neurobiology (2018)
Discipline: NEUROSCIENCE & BEHAVIOR
Keywords: APPswe/PS1dE9; Alzheimer’s disease; Diabetes; High-fat diet; Memantine
Affiliations: 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., Biomedical Research Networking Center in Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain., Unitat de Bioquímica i Biotecnologia, Facultat de Medicina i Ciències de la Salut, Universitat Rovira i Virgili, Reus, Tarragona, Spain., Institut de Neurociencias, Universitat de Barcelona, Barcelona, Spain., Unitat de Farmacia, Tecnologia Farmacèutica i Fisico-química, Facultat de Farmàcia i Ciències de l'Alimentació, Universitat de Barcelona, Barcelona, Spain., Institute of Nanoscience and Nanotechnology (IN2UB), University of Barcelona, Barcelona, Spain., 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., Neurodegenerative Disorders Group, Instituto de Investigacion Hospital 12 de Octubre (i + 12), Madrid, Spain., Department of Biological Sciences, Kent State University, Kent, OH, USA., Departament de Biologia Cel·lular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain., Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona, Spain., Spanish Biomedical Research Center in Diabetes and Associated Metabolic Diseases (CIBERDEM)-Instituto de Salud Carlos III, Barcelona, Spain., Research Institute-Hospital Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain., 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. ., Biomedical Research Networking Center in Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain. ., Institut de Neurociencias, Universitat de Barcelona, Barcelona, Spain. .

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. 

Retracted: No

PubPeer comments:
 Figure 4B u2013 more similar than expected. Could authors check? ![file] , 
 Dear Iago Omanensis: Thank you very much for the comment on the image of the figure. We have carefully examined the GADPH in Figure 4.B and it mistakenly displays an incorrect GAPDH image. We believe that the error occurred during the assembly of the figure when using the Powerpoint program, therefore we apologize for it. However, we would like to emphasize that this error and subsequent accidental change in the original published figure does not affect the results and conclusions of the original manuscript because the objective of this figure is to illustrate a representative image of the results obtained. In our case, during the experiments, the GAPDH obtained should be similar for all the protein samples analyzed, because the amount of protein loaded in each well is the same, however, to minimize any variation during the experiments, the proteins studied are normalized with their respective control protein (GAPDH in our case). Therefore, as we discussed earlier, the graphic error made does not change the results and conclusions of the manuscript. ![file] , 
 May 4, 2020 correction. ![file] ,