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… 
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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.
The multifaceted roles of glycogen synthase kinase 3β in cellular signaling
Aβ amyloidosis induces the initial stage of tau accumulation in APPSw mice
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.
Human Wild-Type Tau Interacts with wingless Pathway Components and Produces Neurofibrillary Pathology in Drosophila
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.
...
...