Glycogen synthase kinase-3β regulates fractalkine production by altering its trafficking from Golgi to plasma membrane: implications for Alzheimer's disease.
Glycogen synthase kinase-3β (GSK-3β) is a serine-threonine kinase implicated in multiple processes and signaling pathways. Its dysregulation is associated with different pathological conditions including Alzheimer's disease (AD). Here we demonstrate how changes in GSK-3β activity and/or levels regulate the production and subsequent secretion of fractalkine, a chemokine involved in the immune response that has been linked to AD and to other different neurological disorders. Treatment of primary cultured neurons with GSK-3β inhibitors such as lithium and AR-A014418 decreased full-length fractalkine in total cell extracts. Opposite effects were observed after neuron transduction with a lentiviral vector overexpressing the kinase. Biotinylation assays showed that those changes mainly affect the plasma membrane-associated form of the protein, an observation that positively correlates with changes in the levels of its soluble form. These effects were confirmed in lithium-treated wild type (wt) mice and in GSK-3β transgenic animals, as well as in brain samples from AD patients, evident as age-dependent (animals) or Braak stage dependent changes (humans) in both the membrane-bound and the soluble forms of the protein. Further immunohistochemical analyses demonstrated how GSK-3β exerts these effects by affecting the trafficking of the chemokine from the Golgi to the plasma membrane, in different and opposite ways when the levels/activity of the kinase are increased or decreased. This work provides for the first time a mechanism linking GSK-3β and fractalkine both in vitro and in vivo, with important implications for neurological disorders and especially for AD, in which levels of this chemokine might be useful as a diagnostic tool.
Department of Clinical Neurosciences, NIHR Biomedical Research Centre, Wellcome Trust-Medical Research Council Stem Cell Institute, University of Cambridge, Clifford Allbutt Building, Cambridge Biosciences Campus, Cambridge, CB2 0PY, UK. af541@cam.ac.uk.|Department of Molecular Neurobiology, Centro de Biología Molecular Severo Ochoa (CSIC-UAM), 28049, Madrid, Spain. af541@cam.ac.uk.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, ISCIII), Madrid, Spain. af541@cam.ac.uk.
Almudena
A
Fuster-Matanzo
Department of Molecular Neurobiology, Centro de Biología Molecular Severo Ochoa (CSIC-UAM), 28049, Madrid, Spain.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, ISCIII), Madrid, Spain.
Jerónimo
J
Jurado-Arjona
Department of Molecular Neurobiology, Centro de Biología Molecular Severo Ochoa (CSIC-UAM), 28049, Madrid, Spain.
Stefano
S
Benvegnù
Department of Molecular Neurobiology, Centro de Biología Molecular Severo Ochoa (CSIC-UAM), 28049, Madrid, Spain.
Esther
E
García
Department of Molecular Neurobiology, Centro de Biología Molecular Severo Ochoa (CSIC-UAM), 28049, Madrid, Spain.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, ISCIII), Madrid, Spain.
Patricia
P
Martín-Maestro
Departament of Cellular and Molecular Biology, Centro de Investigaciones Biológicas, CSIC, 28040, Madrid, Spain.
Raquel
R
Gómez-Sintes
Department of Molecular Neurobiology, Centro de Biología Molecular Severo Ochoa (CSIC-UAM), 28049, Madrid, Spain.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, ISCIII), Madrid, Spain.
Félix
F
Hernández
Department of Molecular Neurobiology, Centro de Biología Molecular Severo Ochoa (CSIC-UAM), 28049, Madrid, Spain. jesus.avila@csic.es.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, ISCIII), Madrid, Spain. jesus.avila@csic.es.
Jesús
J
Ávila
D000544:Alzheimer Disease / Q000378:metabolism*; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism*; D054428:Chemokine CX3CL1 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism*; D006056:Golgi Apparatus / Q000378:metabolism*; D006801:Humans; D008810:Mice, Inbred C57BL; D011485:Protein Binding; D021381:Protein Transport; D012995:Solubility; D022161:Transport Vesicles / Q000378:metabolism; D020691:rab GTP-Binding Proteins / Q000378:metabolism
D054428:Chemokine CX3CL1; D000071679:Glycogen Synthase Kinase 3 beta; D020691:rab GTP-Binding Proteins
Alzheimer’s disease; Fractalkine; GSK-3β; Golgi network; Rab8