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Selective loss of basal forebrain cholinergic neurons by 192 IgG-saporin is associated with decreased phosphorylation of Ser9 glycogen synthase kinase-3β

Hawkes, Cheryl; 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(1) pp. 263–272.

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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 LiCI 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

Item Type: Journal Item
Copyright Holders: 2005 International Society for Neurochemistry
ISSN: 0022-3042
Project Funding Details:
Funded Project NameProject IDFunding Body
Not SetNot SetCanadian Institutes of Health Research
Not SetNot SetAlzheimer Society
Extra Information: cited By 10
Keywords: akt kinase; cell death; cholinergic markers; immunolesion; lithium chloride; tau phosphorylation
Academic Unit/School: Faculty of Science, Technology, Engineering and Mathematics (STEM) > Life, Health and Chemical Sciences
Faculty of Science, Technology, Engineering and Mathematics (STEM)
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Item ID: 44110
Depositing User: Cheryl Hawkes
Date Deposited: 20 Aug 2015 16:35
Last Modified: 07 Dec 2018 10:34
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