Glycogen synthase kinase-3 signaling in Alzheimer's disease

Abstract

Alzheimer's disease (AD) is the most common form of neurodegenerative disorder with dementia, accounting for approximately 70% of the all cases. Currently, 5.8 million people in the U.S. are living with AD and by 2050 this number is expected to double resulting in a significant socio-economic burden. Despite intensive research, the exact mechanisms that trigger AD are still not known and at the present there is no cure for it. In recent years, many signaling pathways associated with AD neuropathology have been explored as possible candidate targets for the treatment of this condition including glycogen synthase kinase-3β (GSK3-β). GSK3-β is considered a key player in AD pathophysiology since dysregulation of this kinase influences all the major hallmarks of the disease including: tau phosphorylation, amyloid-β production, memory, neurogenesis and synaptic function. The present review summarizes the current understanding of the GSK3-β neurobiology with particular emphasis on its effects on specific signaling pathways associated with AD pathophysiology. Moreover, it discusses the feasibility of targeting GSK3-β for AD treatment and provides a summary of the current research effort to develop GSK3-β inhibitors in preclinical and clinical studies.

Keywords: Alzheimer's disease; Amyloid beta; Animal models; GSK-3 beta; Neurodegeneration; Tau protein.

Figure 1.. Role of GSK3-β signaling in AD pathology.

Schematic representation of the potential involvement of GSK3-β in different aspects and pathways relevant to the onset and development of Alzheimer’s disease neuropathology. 1) GSK3-β activation contributes to neurodegeneration by directly promoting tau hyper-phosphorylation. Hyperphosphorylated tau dissociates from the microtubules leading to impaired axonal transport, NFTs formation, neuronal and synaptic dysfunction. 2) GSK3-β promotes amyloid production and accumulation which induces apoptosis and neuronal damage in AD. 3) GSK3-β also displays pro-inflammatory functions; it regulates the biological response of microglia, primary immune cells of the CNS and promotes production of inflammatory molecules. 4) Additionally, GSK3-β play a critical role in the regulation of hippocampal neurogenesis, an important process that supports specific form of learning and memory and known to be affected in AD pathology. 5) Finally, GSK3-β is also involved in synaptic plasticity and memory. Overactivation of this kinase has been linked to inhibition of hippocampal long-term potentiation (LTP), a mechanism required for memory formation.

Figure 2.. Regulation of GSK3-β activity.

GSK3-β exists in an active and in inactive form depending on its phosphorylation status. Two families of enzymes modulate GSK3-β activity: Serine/Threonine and Tyrosine kinases which attach phosphate groups to GSK3-β and phosphatases which remove phosphate groups from GSK3-β protein in response to external stimuli. In vitro and in vivo evidence have shown that, GSK3-β activation is mediated by auto-phosphorylation on tyrosine-216, while its inhibition is mediated by phosphorylation on serine 9 by several kinases including: AKT, protein kinase A and B (PKA-PKB) and P90RSK. GSK3-β phosphorylation on serine 389 by P38 MAPK kinase instead, has been shown to inhibit GSK3-β. Additionally, the phosphate groups added to GSK3-β during phosphorylation can be removed by protein phosphatase PP2A resulting in GSK3-β re-activation.

Figure 3.. GSK3-β interferes with Aβ and tau metabolism.

Increased activity of GSK3-β promotes Aβ formation via two distinct mechanisms: GSK3-β induces BACE1 gene expression via upregulation of NFK-β signaling and modulates γ-secretase activity. 1) The human BACE1 promoter region contains two functional NF-kB-binding sites. In vitro and in vivo evidence have shown that GSK3-β activation is involved in NFK-β/p65 nuclear translocation and binding to the BACE1 promoter sites, ultimately resulting in increased BACE1 protein levels and BACE1 mediated-APP processing and Aβ production. 2) GSK3-β modulates γ-secretase activity by direct interaction and regulation of PS1 activity and cellular localization. Upon GSK3-β phosphorylation, PS1 shows lower binding affinity for N-cadherin and reduced cell-surface expression which alter PS1/γ-secretase substrate specificity. Additionally, GSK3-β is one of the major kinases involved in tau phosphorylation. The addition of a phosphate group on the specific Thr231 residue of tau protein leads to microtubules disassembly and promotes formation of tau oligomers and NFTs contributing to neuronal dysfunction and degeneration.