Selective loss of basal forebrain cholinergic neurons by 192 IgG-saporin is associated with decreased phosphorylation of Ser9 glycogen synthase kinase-3β
Article first published online: 1 AUG 2005
Journal of Neurochemistry
Volume 95, Issue 1, pages 263–272, October 2005
How to Cite
Hawkes, C., Jhamandas, J. H. and Kar, S. (2005), Selective loss of basal forebrain cholinergic neurons by 192 IgG-saporin is associated with decreased phosphorylation of Ser9 glycogen synthase kinase-3β. Journal of Neurochemistry, 95: 263–272. doi: 10.1111/j.1471-4159.2005.03363.x
- Issue published online: 25 AUG 2005
- Article first published online: 1 AUG 2005
- Received April 29, 2005; resubmitted manuscript accepted May 16, 2005.
- Akt kinase;
- cell death;
- cholinergic markers;
- lithium chloride;
- tau phosphorylation
Glycogen synthase kinase-3β (GSK-3β) is a multifunctional enzyme involved in a variety of biological events including development, glucose metabolism and cell death. Its activity is inhibited by phosphorylation of the Ser9 residue and up-regulated by Tyr216 phosphorylation. Activated GSK-3β increases phosphorylation of tau protein and induces cell death in a variety of cultured neurons, whereas phosphorylation of phosphatidylinositol-3 (PI-3) kinase-dependent protein kinase B (Akt), which inhibits GSK-3β activity, is one of the best characterized cell survival signaling pathways. In the present study, the cholinergic immunotoxin 192 IgG-saporin was used to address the potential role of GSK-3β in the degeneration of basal forebrain cholinergic neurons, which are preferentially vulnerable in Alzheimer's disease (AD) brain. GSK-3β co-localized with a subset of forebrain cholinergic neurons and loss of these neurons was accompanied by a transient decrease in PI-3 kinase, phospho-Ser473Akt and phospho-Ser9GSK-3β levels, as well as an increase in phospho-tau levels, in the basal forebrain and hippocampus. Total Akt, GSK-3β, tau and phospho-Tyr216GSK-3β levels were not significantly altered in these brain regions in animals treated with 192 IgG-saporin. Systemic administration of the GSK-3β inhibitor LiCl did not significantly affect cholinergic marker or phospho-Ser9GSK-3β levels in control rats but did preclude 192-IgG saporin-induced alterations in PI-3 kinase/phospho-Akt, phospho-Ser9GSK-3β and phospho-tau levels, and also partly protected cholinergic neurons against the immunotoxin. These results provide the first evidence that increased GSK-3β activity, via decreased Ser9 phosphorylation, can mediate, at least in part, 192-IgG saporin-induced in vivo degeneration of forebrain cholinergic neurons by enhancing tau phosphorylation. The partial protection of these neurons following inhibition of GSK-3β kinase activity suggests a possible therapeutic role for GSK-3β inhibitors in attenuating the loss of basal forebrain cholinergic neurons observed in AD.