Pivotal role of glycogen synthase kinase-3: A therapeutic target for Alzheimer's disease

Maqbool, Mudasir; Mobashir, Mohammad; Hoda, Nasimul

doi:10.1016/j.ejmech.2015.10.018

Cited by 199 publications

(133 citation statements)

References 175 publications

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“…The increased platelet GSK3β activity was reported in patients in early AD stages [29]. The definite role of platelet GSK3β is still unclear, but there is evidence of its involvement in the regulation of platelet activation and τ forms in AD [28][29][30]. The potential of molecular changes related to τ and amyloid pathology in platelets as diagnostic biomarkers is promising and awaits further investigation.…”

Section: Amyloid Cascadementioning

confidence: 99%

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Search for Alzheimer's Disease Biomarkers in Blood Cells: Hypotheses-Driven Approach

et al. 2017

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Current Alzheimer's disease (AD) diagnostics is based on cognitive testing, and detecting amyloid Aβ and τ pathology by brain imaging and assays of cerebrospinal fluid. However, biomarkers identifying complex pathways contributing to pathology are lacking, especially for early AD. Preferably, such biomarkers should be more cost-effective and present in easily available diagnostic tissues, such as blood. Here, we summarize the recent findings of potential early AD molecular diagnostic biomarkers in blood platelets, lymphocytes and erythrocytes. We review molecular alterations which refer to such main hypotheses of AD pathogenesis as amyloid cascade, oxidative and mitochondrial stress, inflammation and alterations in cell cycle regulatory molecules. The major advantage of such biomarkers is the potential ability to indicate individualized therapies in AD patients. Alzheimer's disease (AD) is the most prevalent age-related dementia worldwide and one of the major unmet, increasing medical and economic problems of the modern world. As of 2015, there were an estimated 46.8 million people with dementia worldwide. This number will increase to an estimated 74.7 million in 2030 [1].Among the neuropathological hallmarks of AD are: the progressive loss of brain neurons, synaptic degeneration and the deposition of extracellular amyloid plaques and intracellular neurofibrillary tangles (NFTs) in such regions of the brain as the hippocampus, cortex and amygdala. Amyloid plaques consist mainly of 40-and 42-amino-acid Aβ peptides (Aβ40 and Aβ42). Peptides are proteolytic cleavage products of the Aβ protein precursor (APP) but with no fully elucidated biological function. NFTs are deposits of paired helical filaments composed mainly of hyperphosphorylated τ protein, a microtubule-stabilizing protein that maintains neuronal cell structure and axonal transport. Nevertheless, neither senile plaques nor NFTs are absolute hallmarks of AD dementia, because cognitively intact aged individuals may exhibit both pathological changes upon postmortem brain examination or as assessed by positron emission tomography amyloid and τ imaging agents (amyloid-PET and τ-PET) [2][3][4][5].Clinical AD manifests by aggravating dysfunction and weakening functional cognitive processes, linked to brain neuron loss that is both progressive and permanent [4], and that within several years leads to total dependence on the caregiver and eventually to death. Advances in our knowledge of AD have shown that clinical symptoms usually develop after a long preclinical pathogenic process, lasting for decades, making early AD detection in asymptomatic patients a subject of great interest [4,5]. Increasing proof demonstrates that the therapeutic methods' effectiveness is strictly contingent on the early diagnosis of AD, before the occurrence of massive neuron loss and dementia. This highlights the key importance of biochemical biomarkers for early AD diagnostics. AD diagnostics & demand for novel, improved biomarkersThe broadly accepted recommendations for AD diagnosis...

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Section: Amyloid Cascadementioning

confidence: 99%

“…The activation of GSK3β has been linked both with the pathology of τ and Aβ as GSK3β promotes amyloidogenic cleavage of APP [28]. GSK3β and τ protein expression in platelets is higher compared with other blood cells.…”

Section: Reviewmentioning

confidence: 99%

Search for Alzheimer's Disease Biomarkers in Blood Cells: Hypotheses-Driven Approach

et al. 2017

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“…GSK-3 inhibitors have beneficial effects by reducing the amount of Aβ and the hyperphosphorylation of tau in different models of AD (Maqbool et al, 2015). But beyond these effects, GSK-3 inhibitors are also able to increase Nrf2 activation, so they can exert additional therapeutic effects through this mechanism.…”

Section: Gsk-3 Inhibitors As Nrf2 Activators In Neurodegenerative Dismentioning

confidence: 99%

Nrf2 activation in the treatment of neurodegenerative diseases: a focus on its role in mitochondrial bioenergetics and function

Esteras¹,

Dinkova‐Kostova²,

Abramov³

2016

Biological Chemistry

132

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Abstract:The nuclear factor erythroid-derived 2 (NF-E2)-related factor 2 (Nrf2) is a transcription factor wellknown for its function in controlling the basal and inducible expression of a variety of antioxidant and detoxifying enzymes. As part of its cytoprotective activity, increasing evidence supports its role in metabolism and mitochondrial bioenergetics and function. Neurodegenerative diseases are excellent candidates for Nrf2-targeted treatments. Most neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementia and Friedreich's ataxia are characterized by oxidative stress, misfolded protein aggregates, and chronic inflammation, the common targets of Nrf2 therapeutic strategies. Together with them, mitochondrial dysfunction is implicated in the pathogenesis of most neurodegenerative disorders. The recently recognized ability of Nrf2 to regulate intermediary metabolism and mitochondrial function makes Nrf2 activation an attractive and comprehensive strategy for the treatment of neurodegenerative disorders. This review aims to focus on the potential therapeutic role of Nrf2 activation in neurodegeneration, with special emphasis on mitochondrial bioenergetics and function, metabolism and the role of transporters, all of which collectively contribute to the cytoprotective activity of this transcription factor.

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“…Interestingly, some kinases inhibit their downstream effectors by phosphorylation of their respective substrates. For example, the phosphorylation of glycogen synthase (GS) by glycogen synthase kinase deactivates GS [1]. The pathophysiology of many diseases involves abnormal kinase activity.…”

Section: Introductionmentioning

confidence: 99%

Cross talk of c-Jun N-terminal kinase and p38 map kinase modulate insulin and TNFα-stimulated VCAM-1 expression in rat aorta endothelial cells

Pott¹,

Tsurudome²,

Bui³

et al. 2016

ADMET DMPK

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Pivotal role of glycogen synthase kinase-3: A therapeutic target for Alzheimer's disease

Cited by 199 publications

References 175 publications

Search for Alzheimer's Disease Biomarkers in Blood Cells: Hypotheses-Driven Approach

Search for Alzheimer's Disease Biomarkers in Blood Cells: Hypotheses-Driven Approach

Nrf2 activation in the treatment of neurodegenerative diseases: a focus on its role in mitochondrial bioenergetics and function

Cross talk of c-Jun N-terminal kinase and p38 map kinase modulate insulin and TNFα-stimulated VCAM-1 expression in rat aorta endothelial cells

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