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Front Mol Neurosci. 2018 Aug 28;11:273. doi: 10.3389/fnmol.2018.00273. eCollection 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 APPSw,Ind Mice.

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Molecular Neurobiology Laboratory, Department of Biochemistry and Molecular Biomedicine, Universitat de Barcelona, Barcelona, Spain.
Centro de Investigación en Red, Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain.
Department of Dementia and Higher Brain Function, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
Department de Bioquímica i Biologia Molecular, Institut de Neurociències, Universitat Autònoma de Barcelona, Bellaterra, Spain.
Molecular and Cellular Neurobiotechnology, Institute of Bioengineering of Catalonia, The Barcelona Institute of Science and Technology, Barcelona, Spain.
Department of Cell Biology, Physiology and Immunology, Universitat de Barcelona, Barcelona, Spain.
RG Neuroplasticity, Leibniz Institute for Neurobiology, Magdeburg, Germany.
Leibniz Group Dendritic Organelles and Synaptic Function, Center for Molecular Neurobiology, ZMNH, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
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 Ca2+-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 APPSw,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 signaling of NMDAR to the MAPK pathway and that calcium sensors are important for NMDAR function both in neurons and microglia. Finally, it should be noted that the expression of receptor-calcium sensor complexes, specially those involving NCS1, is altered in neural cells from APPSw,Ind mouse embryos/pups.


Alzheimer’s disease; NCS1; caldendrin; calmodulin; calneuron-1; extracellular signal-regulated kinase; glutamate receptor; proximity ligation assay

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