Glycogen Synthase Kinase-3 Regulates Production of Amyloid-<i>β</i>Peptides and Tau Phosphorylation in Diabetic Rat Brain

Qu, Zhongsen; Li, Liang; Sun, Xiaojiang; Zhao, Yuwu; Zhang, Jin; Geng, Zhi; Fu, Junfen; Ren, Qiangqiang

doi:10.1155/2014/878123

Cited by 39 publications

(27 citation statements)

References 27 publications

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“…In the search for new drug targets, glycogen synthase 3 (GSK-3) has taken center stage for its known involvement in several pathways linked to both BD and diabetes mellitus (Gould et al 2004 ; Ronai et al 2014 ; Huang et al 2014 ; Iwahashi et al 2014 ). In the rat, lithium, a standard treatment for BD, reduces the enzyme’s activity in the hippocampus and improves memory and learning (Qu et al 2014 ). Novel GSK-3 inhibitors are now in preclinical testing (Datusalia and Sharma 2014 ; King et al 2013 ).…”

Section: Discussionmentioning

confidence: 99%

Bipolar disorder and diabetes mellitus: evidence for disease-modifying effects and treatment implications

Charles

Lambert

Kerner

2016

Int J Bipolar Disord

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Background: Bipolar disorder refers to a group of chronic psychiatric disorders of mood and energy levels. While dramatic psychiatric symptoms dominate the acute phase of the diseases, the chronic course is often determined by an increasing burden of co-occurring medical conditions. High rates of diabetes mellitus in patients with bipolar disorder are particularly striking, yet unexplained. Treatment and lifestyle factors could play a significant role, and some studies also suggest shared pathophysiology and risk factors. Objective:In this systematic literature review, we explored data around the relationship between bipolar disorder and diabetes mellitus in recently published population-based cohort studies with special focus on the elderly. Methods:A systematic search in the PubMed database for the combined terms "bipolar disorder" AND "elderly" AND "diabetes" in papers published between January 2009 and December 2015 revealed 117 publications; 7 studies were large cohort studies, and therefore, were included in our review. Results:We found that age-and gender-adjusted risk for diabetes mellitus was increased in patients with bipolar disorder and vice versa (odds ratio range between 1.7 and 3.2). Discussion:Our results in large population-based cohort studies are consistent with the results of smaller studies and chart reviews. Even though it is likely that heterogeneous risk factors may play a role in diabetes mellitus and in bipolar disorder, growing evidence from cell culture experiments and animal studies suggests shared disease mechanisms. Furthermore, disease-modifying effects of bipolar disorder and diabetes mellitus on each other appear to be substantial, impacting both treatment response and outcomes. Conclusions:The risk of diabetes mellitus in patients with bipolar disorder is increased. Our findings add to the growing literature on this topic. Increasing evidence for shared disease mechanisms suggests new disease models that could explain the results of our study. A better understanding of the complex relationship between bipolar disorder and diabetes mellitus could lead to novel therapeutic approaches and improved outcomes.

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Section: Discussionmentioning

confidence: 99%

Bipolar disorder and diabetes mellitus: evidence for disease-modifying effects and treatment implications

Charles

Lambert

Kerner

2016

Int J Bipolar Disord

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“…Hyperphosphorylated tau then aggregates to form neurofibrillary tangles (Avila et al, 2010 ). GSK-3β is also a key mediator of apoptosis suggesting that it might activate neuronal loss in degenerative diseases with increased production of Aβ (Qu et al, 2014 ). Emerging data also shows that PI3K/AKT pathway regulates synaptic plasticity by stimulating excitatory and inhibitory cell membrane receptors, enhances neurotransmitter activities and increases cortical glucose metabolism in the brain regions that are important for learning and memory (Farrar et al, 2005 ).…”

Section: Alzheimer's Disease: Insulin Resistance In the Brainmentioning

confidence: 99%

Alzheimer's Disease and Type 2 Diabetes: A Critical Assessment of the Shared Pathological Traits

2018

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Alzheimer's disease (AD) and Type 2 Diabetes Mellitus (T2DM) are two of the most prevalent diseases in the elderly population worldwide. A growing body of epidemiological studies suggest that people with T2DM are at a higher risk of developing AD. Likewise, AD brains are less capable of glucose uptake from the surroundings resembling a condition of brain insulin resistance. Pathologically AD is characterized by extracellular plaques of Aβ and intracellular neurofibrillary tangles of hyperphosphorylated tau. T2DM, on the other hand is a metabolic disorder characterized by hyperglycemia and insulin resistance. In this review we have discussed how Insulin resistance in T2DM directly exacerbates Aβ and tau pathologies and elucidated the pathophysiological traits of synaptic dysfunction, inflammation, and autophagic impairments that are common to both diseases and indirectly impact Aβ and tau functions in the neurons. Elucidation of the underlying pathways that connect these two diseases will be immensely valuable for designing novel drug targets for Alzheimer's disease.

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“…Thus Wnt signaling leads to stabilization of β-catenin and its translocation to the nucleus where it induces transcription of Wnt target genes. GSK3β also phosphorylates tau and might be the integration point of Aβ and tau induced toxicity [ 6 ].…”

Section: Resultsmentioning

confidence: 99%

Lack of evidence of the interaction of the Aβ peptide with the Wnt signaling cascade in Drosophila models of Alzheimer's disease

Lüchtenborg

Katanaev

2014

Mol Brain

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BackgroundAlzheimer’s disease (AD) is the leading form of dementia worldwide. The Aβ-peptide is believed to be the major pathogenic compound of the disease. Since several years it is hypothesized that Aβ impacts the Wnt signaling cascade and therefore activation of this signaling pathway is proposed to rescue the neurotoxic effect of Aβ.FindingsExpression of the human Aβ42 in the Drosophila nervous system leads to a drastically shortened life span. We found that the action of Aβ42 specifically in the glutamatergic motoneurons is responsible for the reduced survival. However, we find that the morphology of the glutamatergic larval neuromuscular junctions, which are widely used as the model for mammalian central nervous system synapses, is not affected by Aβ42 expression. We furthermore demonstrate that genetic activation of the Wnt signal transduction pathway in the nervous system is not able to rescue the shortened life span or a rough eye phenotype in Drosophila.ConclusionsOur data confirm that the life span is a useful readout of Aβ42 induced neurotoxicity in Drosophila; the neuromuscular junction seems however not to be an appropriate model to study AD in flies. Additionally, our results challenge the hypothesis that Wnt signaling might be implicated in Aβ42 toxicity and might serve as a drug target against AD.

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Glycogen Synthase Kinase-3 Regulates Production of Amyloid-βPeptides and Tau Phosphorylation in Diabetic Rat Brain

Cited by 39 publications

References 27 publications

Bipolar disorder and diabetes mellitus: evidence for disease-modifying effects and treatment implications

Bipolar disorder and diabetes mellitus: evidence for disease-modifying effects and treatment implications

Alzheimer's Disease and Type 2 Diabetes: A Critical Assessment of the Shared Pathological Traits

Lack of evidence of the interaction of the Aβ peptide with the Wnt signaling cascade in Drosophila models of Alzheimer's disease

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