GSK3β Signalling: Casting a Wide Net in Alzheimer’s Disease

@article{Bhat2002GSK3SC,
  title={GSK3$\beta$ Signalling: Casting a Wide Net in Alzheimer’s Disease},
  author={Ratan V Bhat and Samantha L. Budd},
  journal={Neurosignals},
  year={2002},
  volume={11},
  pages={251 - 261}
}
Glycogen synthase kinase-3β (GSK3β) is a kinase that plays a pivotal role in numerous cellular functions from modulation of microtubule dynamics and cell death. It also affects higher functions such as cognition and mood. Deregulation of GSK3β activity in the adult brain is implicated in several CNS disorders, such as affective disorders, schizophrenia, stroke and neurodegenerative diseases, such as Alzheimer’s disease (AD). In AD, GSK3β has a major role in microtubule stability by its ability… 

Figures from this paper

Glycogen Synthase Kinase-3 as a Therapeutic Target for Cognitive Dysfunction in Neuropsychiatric Disorders
TLDR
The role of GSK-3 as a regulator of cognitive-dependent functions is summarised, current preclinical and clinical evidence of the potential of G SKS-3 inhibitors as therapeutic agents for cognitive impairments in neuropsychiatric disorders are examined, and some insight is offered into the current obstacles that are impeding the clinical use of selective GK3 inhibitors in the treatment of cognitive impairment.
The Role of Glycogen Synthase Kinase-3 (GSK-3) in Alzheimer’s Disease
TLDR
The key role that GSK-3 plays in AD pathobiology and the use of G SKS-3 inhibition as a potential therapeutic approach to treat this disease are described.
10 The Role of Glycogen Synthase Kinase-3 ( GSK-3 ) in Alzheimer ’ s Disease
TLDR
The key role that GSK-3 plays in AD pathobiology is described and the use of G SKS-3 inhibition as a potential therapeutic approach to treat this disease is described.
Melatonin in Alzheimer’s Disease: A Latent Endogenous Regulator of Neurogenesis to Mitigate Alzheimer’s Neuropathology
TLDR
The neuroprotective roles of melatonin are summarized by the blockage of Aβ production, Aβ oligomerization and fibrillation, tau hyperphosphorylation, synaptic dysfunction, oxidative stress, and neuronal death during AD progression.
GSK3β: A master switch and a promising target
TLDR
The major developments in the area of GSK3β as a therapeutic target globally and its role in disease physiology are discussed and an overview of the classes of compounds designed for its inhibition are given.
Role of protein kinases in neurodegenerative disease: cyclin-dependent kinases in Alzheimer's disease.
TLDR
The theory that Cdks are involved in the pathogenesis of AD has generated considerable interest, and reports supporting the involvement of both pathways are plentiful, but the story is not yet complete.
Glycogen synthase kinase 3 β ( GSK 3 β ) mediates 6-hydroxydopamine-induced neuronal death
TLDR
It is demonstrated here that 6OHDA evoked endoplasmic reticulum (ER) stress, which was characterized by an up-regulation in the expression of GRP78 and GADD153 (Chop), cleavage of procaspase-12, and phosphorylation of eukaryotic initiation factor-2 α in a human dopaminergic neuronal cell line (SH-SY5Y) and cultured rat cerebellar granule neurons (CGNs).
AZD1080, a novel GSK3 inhibitor, rescues synaptic plasticity deficits in rodent brain and exhibits peripheral target engagement in humans
TLDR
Interestingly, subchronic but not acute administration with AZD1080 reverses MK‐801‐induced deficits, measured by long‐term potentiation in hippocampal slices and in a cognitive test in mice, suggesting that reversal of synaptic plasticity deficits in dysfunctional systems requires longer term modifications of proteins downstream of GSK3β signaling.
Tau and neurofilament proteins in Alzheimer's disease and related cell models
TLDR
P70S6K can regulate tau on both translational and post-translational levels, while the main effect of other kinases, such as GSK-3, is on tau phosphorylation, which suggests that tau antibodies can be used selectively in AD diagnosis as a complement to morphological evaluations.
...
...

References

SHOWING 1-10 OF 136 REFERENCES
Tau protein phosphorylation as a therapeutic target in Alzheimer's disease.
TLDR
Key challenges in developing effective therapeutic agents include identification of the relevant kinase(s) responsible for aberrant tau phosphorylation in AD, synthesis of inhibitors selectively targeting those kinases and establishment of appropriate animal models.
Distribution of Active Glycogen Synthase Kinase 3β (GSK-3β) in Brains Staged for Alzheimer Disease Neurofibrillary Changes
TLDR
Direct in situ evidence is found that neurons with tangle-like inclusions positive for active, but not inactive, GSK-3β appear initially in the Pre-α layer of the entorhinal cortex and extend to other brain regions, coincident with the sequence of the development of neurofibrillary changes.
Distribution of active glycogen synthase kinase 3beta (GSK-3beta) in brains staged for Alzheimer disease neurofibrillary changes.
TLDR
Direct in situ evidence is found that neurons with tangle-like inclusions positive for active, but not inactive, GSK-3beta appear initially in the Pre-alpha layer of the entorhinal cortex and extend to other brain regions, coincident with the sequence of the development of neurofibrillary changes.
Tau in Alzheimer's disease.
Presenilin 1 associates with glycogen synthase kinase-3beta and its substrate tau.
TLDR
Mutations in PS1 that cause Alzheimer's disease increase the ability of PS1 to bind GSK-3beta and, correspondingly, increase its tau-directed kinase activity, and it is proposed that the increased association of GSK3beta with mutant PS1 leads to increased phosphorylation of tau.
The active form of glycogen synthase kinase-3β is associated with granulovacuolar degeneration in neurons in Alzheimer's disease
TLDR
The results suggest that neurons developing GVD sequester an active, potentially deleterious, form of GSK-3 in this compartment and that increased G SK-3 immunoreactivity in a subset of neurons quantitatively differentiates normal aging from AD.
Lithium Reduces Tau Phosphorylation by Inhibition of Glycogen Synthase Kinase-3*
TLDR
Using cultured human NT2N neurons, it is demonstrated that lithium reduces the phosphorylation of t Tau, enhances the binding of tau to microtubules, and promotes microtubule assembly through direct and reversible inhibition of glycogen synthase kinase-3.
...
...