Rabbit Anti-Human GSK3α (a.a. 10-59) Polyclonal antibody

Studies have implicated signaling through glycogen synthase kinase (GSK) 3 alpha/beta in the activation of proatherogenic pathways and the accelerated development of atherosclerosis. By using a mouse model, we examined the role of GSK3 alpha in the development and progression of accelerated atherosclerosis. We crossed Gsk3a/GSK3 alpha-knockout mice with low-density lipoprotein receptor (Ldlr) knockout mice. Five-week-old Ldlr(-/-);Gsk3a(+)/(+), Ldlr(-/-);Gsk3a(+/-), and Ldlr(-/-);Gsk3a(-/-) mice were fed a chow diet or a high-fat diet for 10 weeks and then sacrificed. GSK3 alpha deficiency had no detectible effect on any measured parameters in chow-fed mice. High-fat diet fed Ldlr(-/-) mice that were deficient for GSK3 alpha had significantly less hepatic lipid accumulation and smaller atherosclerotic Lesions (60% smaller in Ldlr(-/-); Gsk3a(+/-) mice, 80% smaller in Ldlr(-/-);Gsk3a(-/-) mice; P < 0.05), compared with Ldlr(-/-);Gsk3a(+/+) controls. GSK3 alpha deficiency was associated with a significant increase in plasma IL-10 concentration and IL-10 expression in isolated macrophages. A twofold to threefold enhancement in endoplasmic reticulum stress-induced IL-10 expression was observed in Thp-1 derived macrophages that were pretreated with the GSK3 alpha/beta inhibitor CT99021. Together, these results suggest that GSK3 alpha plays a pro-atherogenic role, possibly by mediating the effects of endoplasmic reticulum stress in the activation of pro-atherogenic pathways.

Glycogen synthase kinase-3 (GSK-3) dysregulation has been implicated in nigral dopaminergic neurodegeneration, one of the main pathological features of Parkinson's disease (PD). The two isoforms, GSK-3 alpha and GSK-3 beta, have both been suggested to play a detrimental role in neuronal death. To date, several studies have focused on the role of GSK-3 beta on PD pathogenesis, while the role of GSK-3 alpha has been largely overlooked. Here, we reportin situobservations that both GSK-3 alpha and GSK-3 beta are dephosphorylated at a negatively acting regulatory serine, indicating kinase activation, selectively in nigral dopaminergic neurons following exposure of mice to 1-methyl-4-pheny-1,2,3,6-tetrahydropyridine (MPTP). To identify whether GSK-3 alpha and GSK-3 beta display functional redundancy in regulating parkinsonian dopaminergic cell death, we analysed dopaminergic neuron-specific Gsk3anull (Gsk3a(Delta Dat)) and Gsk3b null (Gsk3b(Delta Dat)) mice, respectively. We found that Gsk3b(Delta Dat), but not Gsk3a(Delta Dat), showed significant resistance to MPTP insult, revealing non-redundancy of GSK-3 alpha and GSK-3 beta in PD pathogenesis. In addition, we tested the neuroprotective effect of tideglusib, the most clinically advanced inhibitor of GSK-3, in the MPTP model of PD. Administration of higher doses (200 mg/kg and 500 mg/kg) of tideglusib exhibited significant neuroprotection, whereas 50 mg/kg tideglusib failed to prevent dopaminergic neurodegeneration from MPTP toxicity. Administration of 200 mg/kg tideglusib improved motor symptoms of MPTP-treated mice. Together, these data demonstrate GSK-3 beta and not GSK-3 alpha is critical for parkinsonian neurodegeneration. Our data support the view that GSK-3 beta acts as a potential therapeutic target in PD and tideglusib would be a candidate drug for PD neuroprotective therapy.