| First Author | Fuster-Matanzo A | Year | 2017 |
| Journal | Cell Mol Life Sci | Volume | 74 |
| Issue | 6 | Pages | 1153-1163 |
| PubMed ID | 27832289 | Mgi Jnum | J:314969 |
| Mgi Id | MGI:6822889 | Doi | 10.1007/s00018-016-2408-6 |
| Citation | Fuster-Matanzo A, et al. (2017) Glycogen synthase kinase-3beta regulates fractalkine production by altering its trafficking from Golgi to plasma membrane: implications for Alzheimer's disease. Cell Mol Life Sci 74(6):1153-1163 |
| abstractText | Glycogen synthase kinase-3beta (GSK-3beta) 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-3beta 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-3beta 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-3beta 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-3beta 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-3beta 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. |
