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Creator |
d64a4c8b9d6fb32d441f1cd9c453d93b |
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Creator |
ext-2530ea4ac550013b8a6c1e6ab1368ca1 |
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Creator |
ext-82f555a45873abe479764d5e35d71a69 |
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Date |
2005 |
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Is Part Of |
repository |
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Is Part Of |
p00223042 |
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abstract |
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 Ser<sup>9</sup> residue and up-regulated
by Tyr<sup>216</sup> 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-Ser<sup>473</sup>Akt and phospho-Ser<sup>9</sup>GSK-3β
levels, as well as an increase in phospho-tau levels, in the basal forebrain and hippocampus.
Total Akt, GSK-3β, tau and phospho-Tyr<sup>216</sup>GSK-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-Ser<sup>9</sup>GSK-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 Ser<sup>9</sup> 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 |
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authorList |
authors |
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issue |
1 |
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status |
peerReviewed |
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volume |
95 |
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type |
AcademicArticle |
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type |
Article |
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label |
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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label |
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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Title |
Selective loss of basal forebrain cholinergic neurons by 192 IgG-saporin is associated
with decreased phosphorylation of Ser9 glycogen synthase kinase-3β |
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in dataset |
oro |