Glycogen synthase kinase-3β regulates fractalkine production by altering its trafficking from Golgi to plasma membrane: implications for Alzheimer’s disease

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• 作者：Almudena Fuster-Matanzo ; Jerónimo Jurado-Arjona…
• 关键词：GSK ; 3β ; Fractalkine ; Golgi network ; Rab8 ; Alzheimer’s disease
• 刊名：Cellular and Molecular Life Sciences
• 出版年：2017
• 出版时间：March 2017
• 年：2017
• 卷：74
• 期：6
• 页码：1153-1163
• 全文大小：5030KB
• 刊物类别：Biomedical and Life Sciences
• 刊物主题：Cell Biology; Biomedicine, general; Life Sciences, general; Biochemistry, general;
• 出版者：Springer International Publishing
• ISSN：1420-9071
• 卷排序：74

文摘

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.