ORIGINAL RESEARCH published: 28 August 2018 doi: 10.3389/fnmol.2018.00273 Edited by: Inmaculada Maria Gonzalez-Gonzalez, University of Central Lancashire, United Kingdom Reviewed by: Salvador Sierra San Nicolás, Icahn School of Medicine at Mount Sinai, United States Ana Luisa Carvalho, University of Coimbra, Portugal Fabio Blandini, Fondazione Mondino Istituto Neurologico Nazionale a Carattere Scientifico (IRCCS), Italy *Correspondence: Rafael Franco rfranco@ub.edu; rfranco123@gmail.com Gemma Navarro dimartts@hotmail.com Received: 18 March 2018 Accepted: 18 July 2018 Published: 28 August 2018 Citation: Franco R, Aguinaga D, Reyes I, Canela EI, Lillo J, Tarutani A, Hasegawa M, del Ser-Badia A, del Rio JA, Kreutz MR, Saura CA and Navarro G (2018) N-Methyl-D-Aspartate Receptor Link to the MAP Kinase Pathway in Cortical and Hippocampal Neurons and Microglia Is Dependent on Calcium Sensors and Is Blocked by α-Synuclein, Tau, and Phospho-Tau in Non-transgenic and Transgenic APP Sw,Ind Mice. Front. Mol. Neurosci. 11:273. doi: 10.3389/fnmol.2018.00273 N-Methyl-D-Aspartate Receptor Link to the MAP Kinase Pathway in Cortical and Hippocampal Neurons and Microglia Is Dependent on Calcium Sensors and Is Blocked by α-Synuclein, Tau, and Phospho-Tau in Non-transgenic and Transgenic APP Sw,Ind Mice Rafael Franco 1,2 * , David Aguinaga 1,2 , Irene Reyes 1,2 , Enric I. Canela 1,2 , Jaume Lillo 1 , Airi Tarutani 3 , Masato Hasegawa 3 , Anna del Ser-Badia 2,4 , José A. del Rio 2,5,6 , Michael R. Kreutz 7,8 , Carlos A. Saura 2,4 and Gemma Navarro 2,9 * 1 Molecular Neurobiology Laboratory, Department of Biochemistry and Molecular Biomedicine, Universitat de Barcelona, Barcelona, Spain, 2 Centro de Investigación en Red, Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain, 3 Department of Dementia and Higher Brain Function, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan, 4 Department de Bioquímica i Biologia Molecular, Institut de Neurociències, Universitat Autònoma de Barcelona, Bellaterra, Spain, 5 Molecular and Cellular Neurobiotechnology, Institute of Bioengineering of Catalonia, The Barcelona Institute of Science and Technology, Barcelona, Spain, 6 Department of Cell Biology, Physiology and Immunology, Universitat de Barcelona, Barcelona, Spain, 7 RG Neuroplasticity, Leibniz Institute for Neurobiology, Magdeburg, Germany, 8 Leibniz Group Dendritic Organelles and Synaptic Function, Center for Molecular Neurobiology, ZMNH, University Medical Center Hamburg-Eppendorf, Hamburg, Germany, 9 Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Universitat de Barcelona, Barcelona, Spain N-methyl-D-aspartate receptors (NMDARs) respond to glutamate to allow the influx of calcium ions and the signaling to the mitogen-activated protein kinase (MAPK) cascade. Both MAPK- and Ca 2+ -mediated events are important for both neurotransmission and neural cell function and fate. Using a heterologous expression system, we demonstrate that NMDAR may interact with the EF-hand calcium-binding proteins calmodulin, calneuron-1, and NCS1 but not with caldendrin. NMDARs were present in primary cultures of both neurons and microglia from cortex and hippocampus. Calmodulin in microglia, and calmodulin and NCS1 in neurons, are necessary for NMDA-induced MAP kinase pathway activation. Remarkably, signaling to the MAP kinase pathway was blunted in primary cultures of cortical and hippocampal neurons and microglia from wild-type animals by proteins involved in neurodegenerative diseases: α-synuclein, Tau, and p-Tau. A similar blockade by pathogenic proteins was found using samples from the APP Sw,Ind transgenic Alzheimer’s disease model. Interestingly, a very marked increase in NMDAR–NCS1 complexes was identified in neurons and a marked increase of both NMDAR–NCS1 and NMDAR–CaM complexes was identified in microglia from the transgenic mice. The results show that α-synuclein, Tau, and p-Tau disrupt the Frontiers in Molecular Neuroscience | www.frontiersin.org 1 August 2018 | Volume 11 | Article 273