Increased Glucose Transport into Neurons Rescues Aβ Toxicity in Drosophila

Niccoli, Teresa; Cabecinha, Melissa; Tillmann, Anna; Kerr, Fiona; Wong, Chi T.; Cardenes, Dalia; Vincent, Alec J; Bettedi, Lucia; Li, Li; Grönke, Sebastian; Dols, Jacqueline; Partridge, Linda

doi:10.1016/j.cub.2016.09.018

Cited by 28 publications

(37 citation statements)

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“…The effect of Wnt3a treatment was significant after 15 s of exposure, and the time-dependent effect was blocked by co-incubation with Dkk1. The IC 50 value was similar to the values reported for GLUTs. The effect of Wnt3a was independent of both transcription and synaptic effects of Wnt3a and was blocked by co-treatment with Dkk1, AZD5363, and TCS183.…”

Section: Discussionsupporting

confidence: 77%

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Activation of Wnt Signaling in Cortical Neurons Enhances Glucose Utilization through Glycolysis

Cisternas

Salazar

Silva-Álvarez

et al. 2016

Journal of Biological Chemistry

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Edited by Jeffrey E. PessinThe Wnt signaling pathway is critical for a number of functions in the central nervous system, including regulation of the synaptic cleft structure and neuroprotection against injury. Deregulation of Wnt signaling has been associated with several brain pathologies, including Alzheimer's disease. In recent years, it has been suggested that the Wnt pathway might act as a central integrator of metabolic signals from peripheral organs to the brain, which would represent a new role for Wnt signaling in cell metabolism. Energy metabolism is critical for normal neuronal function, which mainly depends on glucose utilization. Brain energy metabolism is important in almost all neurological disorders, to which a decrease in the capacity of the brain to utilize glucose has been linked. However, little is known about the relationship between Wnt signaling and neuronal glucose metabolism in the cellular context. In the present study, we found that acute treatment with the Wnt3a ligand induced a large increase in glucose uptake, without changes in the expression or localization of glucose transporter type 3. In addition, we observed that Wnt3a treatment increased the activation of the metabolic sensor Akt. Moreover, we observed an increase in the activity of hexokinase and in the glycolytic rate, and both processes were dependent on activation of the Akt pathway. Furthermore, we did not observe changes in the activity of glucose-6-phosphate dehydrogenase or in the pentose phosphate pathway. The effect of Wnt3a was independent of both the transcription of Wnt target genes and synaptic effects of Wnt3a. Together, our results suggest that Wnt signaling stimulates glucose utilization in cortical neurons through glycolysis to satisfy the high energy demand of these cells.

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Section: Discussionsupporting

confidence: 77%

“…2A). We found that the IC 50 value of the effect of Cyt B on the uptake of [2-3 H]DG was 0.70 Ϯ 0.06 M. This finding is consistent with glucose transport through GLUTs (31) (Fig. 2A) 6 cells.…”

Section: Effects Of the Acute Wnt3asupporting

confidence: 79%

Activation of Wnt Signaling in Cortical Neurons Enhances Glucose Utilization through Glycolysis

Cisternas

Salazar

Silva-Álvarez

et al. 2016

Journal of Biological Chemistry

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“…It has been demonstrated that the exogenous stimulation of the glucose metabolism can rescue the cognitive performance in AD patients (Baker et al 2011;Craft et al 2012;Parthsarathy and Holscher 2013). Likewise, the ability of increased glucose metabolism to improve cognitive performance or rescue neuronal cells against the toxicity of Ab has been described in several model organisms, including mice, rats and Drosophila (Niccoli et al 2016;Liu et al 2017). This further demonstrates the close relationship between the deregulation of cerebral glucose metabolism and the cognitive failures described in AD.…”

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confidence: 80%

Wnt‐induced activation of glucose metabolism mediates the in vivo neuroprotective roles of Wnt signaling in Alzheimer disease

Cisternas

Zolezzi

Martínez

et al. 2018

Journal of Neurochemistry

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Dysregulated Wnt signaling is linked to major neurodegenerative diseases, including Alzheimer disease (AD). In mouse models of AD, activation of the canonical Wnt signaling pathway improves learning/memory, but the mechanism for this remains unclear. The decline in brain function in AD patients correlates with reduced glucose utilization by neurons. Here, we test whether improvements in glucose metabolism mediate the neuroprotective effects of Wnt in AD mouse model. APPswe/PS1dE9 transgenic mice were used to model AD, Andrographolide or Lithium was used to activate Wnt signaling, and cytochalasin B was used to block glucose uptake. Cognitive function was assessed by novel object recognition and memory flexibility tests. Glucose uptake and the glycolytic rate were determined using radiotracer glucose. The activities of key enzymes of glycolysis such as hexokinase and phosphofructokinase, Adenosine triphosphate (ATP)/Adenosine diphosphate (ADP) levels and the pentose phosphate pathway and activity of glucose‐6 phosphate dehydrogenase were measured. Wnt activators significantly improved brain glucose utilization and cognitive performance in transgenic mice. Wnt signaling enhanced glucose metabolism by increasing the expression and/or activity of hexokinase, phosphofructokinase and AMP‐activated protein kinase. Inhibiting glucose uptake partially abolished the beneficial effects of Wnt signaling on learning/memory. Wnt activation also enhanced glucose metabolism in cortical and hippocampal neurons, as well as brain slices derived from APPswe/PS1E9 transgenic mice. Combined, these data provide evidence that the neuroprotective effects of Wnt signaling in AD mouse models result, at least in part, from Wnt‐mediated improvements in neuronal glucose metabolism.

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“…With this respect, it is interesting to note that the glucose transporters GluT1 and GluT3 have been reported to be impaired in neurodegenerative diseases such as Huntington's disease (Morea et al, 2017) or Alzheimer 's disease (Mark, Pang, Geddes, Uchida, & Mattson, 1997;Shah, Desilva, & Abbruscato, 2012). More precisely, increased glucose transport is able to rescue a Drosophila model of Ab toxicity (Niccoli et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Glial lipid droplets and neurodegeneration in a Drosophila model of complex I deficiency

Cabirol-Pol

Khalil

Rival

et al. 2017

Glia

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Mitochondrial defects associated with respiratory chain complex I deficiency lead to heterogeneous fatal syndromes. While the role of NDUFS8, an essential subunit of the core assembly of the complex I, is established in mitochondrial diseases, the mechanisms underlying neuropathology are poorly understood. We developed a Drosophila model of NDUFS8 deficiency by knocking down the expression of its fly homologue in neurons or in glial cells. Downregulating ND23 in neurons resulted in shortened lifespan, and decreased locomotion. Although total brain ATP levels were decreased, histological analysis did not reveal any signs of neurodegeneration except for photoreceptors of the retina. Interestingly, ND23 deficiency-associated phenotypes were rescued by overexpressing the glucose transporter hGluT3 demonstrating that boosting glucose metabolism in neurons was sufficient to bypass altered mitochondrial functions and to confer neuroprotection. We then analyzed the consequences of ND23 knockdown in glial cells. In contrast to neuronal knockdown, loss of ND23 in glia did not lead to significant behavioral defects nor to reduced lifespan, but induced brain degeneration, as visualized by numerous vacuoles found all over the nervous tissue. This phenotype was accompanied by the massive accumulation of lipid droplets at the cortex-neuropile boundaries, suggesting an alteration of lipid metabolism in glia. These results demonstrate that complex I deficiency triggers metabolic alterations both in neurons and glial cells which may contribute to the neuropathology.

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Increased Glucose Transport into Neurons Rescues Aβ Toxicity in Drosophila

Abstract: . Electrical hyperexcitation of lateral ventral pacemaker neurons desynchronizes downstream circadian oscillators in the fly circadian circuit and induces multiple behavioral periods.

Cited by 28 publications

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Activation of Wnt Signaling in Cortical Neurons Enhances Glucose Utilization through Glycolysis

Activation of Wnt Signaling in Cortical Neurons Enhances Glucose Utilization through Glycolysis

Wnt‐induced activation of glucose metabolism mediates the in vivo neuroprotective roles of Wnt signaling in Alzheimer disease

Glial lipid droplets and neurodegeneration in a Drosophila model of complex I deficiency

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