title: Selective loss of basal forebrain cholinergic neurons by 192 IgG-saporin is associated with decreased phosphorylation of Ser glycogen synthase kinase-3beta.
abstract: Glycogen synthase kinase-3beta (GSK-3beta) 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-3beta 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-3beta 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-3beta in the degeneration of basal forebrain cholinergic neurons, which are preferentially vulnerable in Alzheimer's disease (AD) brain. GSK-3beta 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-3beta levels, as well as an increase in phospho-tau levels, in the basal forebrain and hippocampus. Total Akt, GSK-3beta, tau and phospho-Tyr216GSK-3beta levels were not significantly altered in these brain regions in animals treated with 192 IgG-saporin. Systemic administration of the GSK-3beta inhibitor LiCl did not significantly affect cholinergic marker or phospho-Ser9GSK-3beta levels in control rats but did preclude 192-IgG saporin-induced alterations in PI-3 kinase/phospho-Akt, phospho-Ser9GSK-3beta and phospho-tau levels, and also partly protected cholinergic neurons against the immunotoxin. These results provide the first evidence that increased GSK-3beta 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-3beta kinase activity suggests a possible therapeutic role for GSK-3beta inhibitors in attenuating the loss of basal forebrain cholinergic neurons observed in AD.
authors.affiliation: Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.
authors.forename: C
authors.initials: C
authors.lastname: Hawkes
authors.forename: J H
authors.initials: JH
authors.lastname: Jhamandas
authors.forename: S
authors.initials: S
authors.lastname: Kar
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology*; D018678:Cholinergic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D002799:Cholinergic Fibers / Q000187:drug effects*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D000922:Immunotoxins / Q000008:administration & dosage / Q000494:pharmacology*; D007276:Injections, Intraventricular; D018021:Lithium Chloride / Q000494:pharmacology; D008297:Male; D009699:N-Glycosyl Hydrolases; D009410:Nerve Degeneration / Q000139:chemically induced*; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D016548:Prosencephalon / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D054789:Ribosome Inactivating Proteins, Type 1; D000076985:Saporins; D016875:tau Proteins / Q000378:metabolism
chemical_list: C085696:192 IgG-saporin; D000911:Antibodies, Monoclonal; D018678:Cholinergic Agents; D000922:Immunotoxins; D018696:Neuroprotective Agents; D054789:Ribosome Inactivating Proteins, Type 1; D016875:tau Proteins; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3; D009699:N-Glycosyl Hydrolases; D000076985:Saporins; D018021:Lithium Chloride