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Selective loss of basal forebrain cholinergic neurons by 192 IgG‐saporin is associated with decreased phosphorylation of Ser 9 glycogen synthase kinase‐3β
Author(s) -
Hawkes C.,
Jhamandas J. H.,
Kar S.
Publication year - 2005
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2005.03363.x
Subject(s) - gsk 3 , cholinergic neuron , basal forebrain , phosphorylation , protein kinase b , medicine , biology , cholinergic , endocrinology , forebrain , glycogen synthase , saporin , kinase , gsk3b , tau protein , microbiology and biotechnology , chemistry , biochemistry , alzheimer's disease , central nervous system , immunotoxin , cytotoxicity , in vitro , disease
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 9 residue and up‐regulated by Tyr 216 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 473 Akt and phospho‐Ser 9 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 216 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 LiCl did not significantly affect cholinergic marker or phospho‐Ser 9 GSK‐3β levels in control rats but did preclude 192‐IgG saporin‐induced alterations in PI‐3 kinase/phospho‐Akt, phospho‐Ser 9 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 9 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.