Unravelling the Role of Glycogen Synthase Kinase-3 in Alzheimer’s Disease-Related Epileptic Seizures

Lin, Runxuan; Jones, Nigel C.; Kwan, Patrick

doi:10.3390/ijms21103676

Cited by 17 publications

(17 citation statements)

References 101 publications

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“…In this review, we propose that the glutamate-glutamine cycle plays a role in the pathogenesis of epilepsy in AD. Although other mechanisms may be very relevant, 26,27 the following section will discuss the evidence from the literature on the role of alterations to the glutamate-glutamine cycle in the pathogenesis of AD and epilepsy.…”

Section: The Glutamate-glutamine Cyclementioning

confidence: 99%

Astrocyte and glutamate involvement in the pathogenesis of epilepsy in Alzheimer's disease

2021

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Alzheimer's disease (AD) can increase the risk of epilepsy by up to 10-fold compared to healthy age-matched controls. However, the pathological mechanisms that underlie this increased risk are poorly understood. Because disruption in brain glutamate homeostasis has been implicated in both AD and epilepsy, this might play a mechanistic role in the pathogenesis of epilepsy in AD. Prior to the formation of amyloid beta (Aβ) plaques, the brain can undergo pathological changes as a result of increased production of amyloid precursor protein (APP) and Aβ oligomers. Impairments in the glutamate uptake ability of astrocytes due to astrogliosis are hypothesized to be an early event occurring before Aβ plaque formation. Astrogliosis may increase the susceptibility to epileptogenesis of the brain via accumulation of extracellular glutamate and resulting excitotoxicity. Here we hypothesize that Aβ oligomers and proinflammatory cytokines can cause astrogliosis and accumulation of extracellular glutamate, which then contribute to the pathogenesis of epilepsy in AD. In this review article, we consider the evidence supporting a potential role of dysfunction of the glutamateglutamine cycle and the astrocyte in the pathogenesis of epilepsy in AD.

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Section: The Glutamate-glutamine Cyclementioning

confidence: 99%

Astrocyte and glutamate involvement in the pathogenesis of epilepsy in Alzheimer's disease

2021

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“…Alzheimer's disease (AD) is the most prevalent form of dementia (Lin, Jones et al, 2020). This health problem results in malignant neurological disorder along with cognitive, functional, and behavioral changes progressively and irreversibly.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of GSK_3β by Iridoid Glycosides of Snowberry (Symphoricarpos albus) Effective in the Treatment of Alzheimer’s Disease Using Computational Drug Design Methods

et al. 2021

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The inhibition of glycogen synthase kinase-3β (GSK-3β) activity prevents tau hyperphosphorylation and binds it to the microtubule network. Therefore, a GSK-3β inhibitor may be a recommended drug for Alzheimer’s treatment. In silico methods are currently considered as one of the fastest and most cost-effective available alternatives for drug/design discovery in the field of treatment. In this study, computational drug design was conducted to introduce compounds that play an effective role in inhibiting the GSK-3β enzyme by molecular docking and molecular dynamics simulation. The iridoid glycosides of the common snowberry (Symphoricarpos albus), including loganin, secologanin, and loganetin, are compounds that have an effect on improving memory and cognitive impairment and the results of which on Alzheimer’s have been studied as well. In this study, in the molecular docking phase, loganin was considered a more potent inhibitor of this protein by establishing a hydrogen bond with the ATP-binding site of GSK-3β protein and the most negative binding energy to secologanin and loganetin. Moreover, by molecular dynamics simulation of these ligands and GSK-3β protein, all structures were found to be stable during the simulation. In addition, the protein structure represented no change and remained stable by binding ligands to GSK-3β protein. Furthermore, loganin and loganetin have higher binding free energy than secologanin; thus, these compounds could effectively bind to the active site of GSK-3β protein. Hence, loganin and loganetin as iridoid glycosides can be effective in Alzheimer’s prevention and treatment, and thus, further in vitro and in vivo studies can focus on these iridoid glycosides as an alternative treatment.

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“…Glycogen synthase kinase-3β (GSK-3β) is an important therapeutic target for a wide range of neurological conditions. GSK-3β dysfunction is known or proposed to be implicated in bipolar disorder (BD), Parkinson’s disease, epilepsy, and Alzheimer’s disease (AD) (according to the prominent tau hyperphosphorylation hypothesis). − Consequentially, GSK-3β is an attractive target for inhibitors to treat these conditions, − and some have even entered clinical trials . However, no recent efforts have yet passed, encountering problems with toxicity and efficacy .…”

Section: Introductionmentioning

confidence: 99%

Contrasting Effects of Inhibitors Li⁺ and Be²⁺ on Catalytic Cycle of Glycogen Synthase Kinase-3β

2021

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Ionic lithium shows rare effectiveness for treating bipolar disorder and is a promising drug for treating neurodegenerative diseases. Unfortunately, lithium suffers from significant drawbacks as a drug, mainly a narrow therapeutic window. Among the different targets of lithium, glycogen synthase kinase 3β (GSK-3β) might be the one responsible for its therapeutic effects. Developing alternative, selective inhibitors of this kinase could avoid lithium side effects, but efforts to do so have met little success so far. A detailed, atomistic understanding of Li + inhibition and a more detailed understanding of the phosphorylation reaction GSK-3β catalyzes would therefore facilitate the development of new drugs. In this study, we use extensive sampling of catalytic states with our mixed quantum-classical dynamics method QM/DMD and binding affinities from a competitive metal affinity (CMA) approach to fill out the atomic scale picture of Li + GSK-3β inhibition. We compare Li + action with Be 2+ , another known inhibitor, and find our results in agreement with in-vitro kinetics studies. Ultimately, our simulations show that Li + inhibition is driven primarily by directly decreasing the reaction rate of the phosphorylation step, rather than reducing catalytic turnover through tight binding to different GSK-3β states like Be 2+ inhibition. The effect of these metals derive from electrostatic differences and especially their smaller atomic radii compared to the native Mg 2+ and thus provides insight for the development of GSK-3β inhibitors based on other paradigms.

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Unravelling the Role of Glycogen Synthase Kinase-3 in Alzheimer’s Disease-Related Epileptic Seizures

Cited by 17 publications

References 101 publications

Astrocyte and glutamate involvement in the pathogenesis of epilepsy in Alzheimer's disease

Astrocyte and glutamate involvement in the pathogenesis of epilepsy in Alzheimer's disease

Inhibition of GSK_3β by Iridoid Glycosides of Snowberry (Symphoricarpos albus) Effective in the Treatment of Alzheimer’s Disease Using Computational Drug Design Methods

Contrasting Effects of Inhibitors Li⁺ and Be²⁺ on Catalytic Cycle of Glycogen Synthase Kinase-3β

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Unravelling the Role of Glycogen Synthase Kinase-3 in Alzheimer’s Disease-Related Epileptic Seizures

Cited by 17 publications

References 101 publications

Astrocyte and glutamate involvement in the pathogenesis of epilepsy in Alzheimer's disease

Astrocyte and glutamate involvement in the pathogenesis of epilepsy in Alzheimer's disease

Inhibition of GSK_3β by Iridoid Glycosides of Snowberry (Symphoricarpos albus) Effective in the Treatment of Alzheimer’s Disease Using Computational Drug Design Methods

Contrasting Effects of Inhibitors Li+ and Be2+ on Catalytic Cycle of Glycogen Synthase Kinase-3β

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Contrasting Effects of Inhibitors Li⁺ and Be²⁺ on Catalytic Cycle of Glycogen Synthase Kinase-3β