TY - JOUR

T1 - Selective loss of basal forebrain cholinergic neurons by 192 IgG-saporin is associated with decreased phosphorylation of Ser9 glycogen synthase kinase-3β

AU - Hawkes, C.

AU - Jhamandas, J. H.

AU - Kar, Satyabrata

PY - 2005/10/1

Y1 - 2005/10/1

N2 - 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.

AB - 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.

KW - Akt kinase

KW - Cell death

KW - Cholinergic markers

KW - Immunolesion

KW - Lithium chloride

KW - Tau phosphorylation

U2 - 10.1111/j.1471-4159.2005.03363.x

DO - 10.1111/j.1471-4159.2005.03363.x

M3 - Journal article

C2 - 16181430

AN - SCOPUS:25644439973

VL - 95

SP - 263

EP - 272

JO - Journal of Neurochemistry

JF - Journal of Neurochemistry

SN - 0022-3042

IS - 1

ER -