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

Cisternas, Pedro; Salazar, Paulina; Silva-Álvarez, Carmen; Barros, L. Felipe; Inestrosa, Nibaldo C.

doi:10.1074/jbc.m116.735373

Cited by 52 publications

(52 citation statements)

References 100 publications

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“…The reaction was stopped by the addition of 10% trichloroacetic acid (TCA, cat: T6399), and the generation of NADPH was measured at 340 nm (Cisternas et al . ). All the reagents were purchased from Sigma‐Aldrich.…”

Section: Methodsmentioning

confidence: 97%

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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Section: Methodsmentioning

confidence: 97%

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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“…In this regard, we have recently demonstrated that the loss of Wnt signalling favours the appearance of several pathological markers linked to AD in a wild-type murine model [102]. Moreover, we found that Wnt signalling is involved in the neuronal energy metabolism and that its activation rescues energy imbalance because of improved glucose utilisation [103]. On the other hand, Wnt signalling also plays a relevant role in PD.…”

Section: Wnt Signalling Pathwaymentioning

confidence: 82%

Molecular Basis of Neurodegeneration: Lessons from Alzheimer’s and Parkinson’s Diseases

Zolezzi¹,

Bastías-Candia²,

Inestrosa³

2019

Recent Advances in Neurodegeneration

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Alzheimer's disease (AD) and Parkinson's disease (PD) constitute the main causes of dementia worldwide and the major health threats to elderly people. Moreover, with the ageing of the global population, neurodegenerative disorders, such as AD and PD, constitute a major public health issue. Regrettably, significant advances regarding the molecular aspects of these diseases have not yet been translated into real improvements in AD/PD therapeutics. In this regard, both AD and PD are highly complex and involve critical molecular events governing the establishment and progression of each disease. Moreover, molecular alterations trigger pathophysiological cascades involving the immune/inflammatory response, oxidative stress, and mitochondrial dysfunction, among others, ultimately leading to neuronal death. Similarly, these alterations also affect glial cells and brain vasculature, which contribute directly to the progression of these disorders. Accordingly, the present paper aims to summarise the main molecular elements related to AD and PD as well as the pathophysiological implications of such alterations to improve our understanding of the cellular and molecular responses observed during neurodegeneration. We believe that providing a more comprehensive view of the pathophysiological cascade, including neurons and glial cells, might prompt researchers to widen neurodegenerative disorder research and therapeutic approaches.

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“…WNT3A is a Wnt ligand, activating The Wnt signaling pathway [21]. It has been reported that WNT3A is critical for The development and function of The nervous system [22], as well as for glucose metabolism in cortical neurons [23]. Thus, DTMUV may affect The development of nervous system through inhibition of WNT3A.…”

Section: Genes Related To Nervous Systemmentioning

confidence: 99%

Transcriptome Analysis Reveals the Neuro-Immune Interactions in Duck Tembusu Virus-Infected Brain

Zhang

Huang

et al. 2020

IJMS

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The duck Tembusu virus (DTMUV) is a mosquito-borne flavivirus. It causes severe symptoms of egg-drop, as well as neurological symptoms and brain damage in ducks. However, the specific molecular mechanisms of DTMUV-induced neurovirulence and host responses in the brain remain obscure. To better understand the host–pathogen and neuro-immune interactions of DTMUV infection, we conducted high-throughput RNA-sequencing to reveal the transcriptome profiles of DTMUV-infected duck brain. Totals of 117, 212, and 150 differentially expressed genes (DEGs) were identified at 12, 24, and 48 h post infection (hpi). Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses uncovered genes and pathways related to the nervous system and immune responses in duck brain. Neuro-related genes, including WNT3A, GATA3, and CHRNA6, were found to be significantly downregulated. RIG-I-like receptors (DHX58, IFIH1) and Toll-like receptors (TLR2 and TLR3) were activated, inducing the expression of 22 interferon stimulated genes (ISGs) and antigen-processing and -presenting genes (TAP1 and TAP2) in the brain. Our research provides comprehensive information for the molecular mechanisms of neuro-immune and host–pathogen interactions of DTMUV.

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

Cited by 52 publications

References 100 publications

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

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

Molecular Basis of Neurodegeneration: Lessons from Alzheimer’s and Parkinson’s Diseases

Transcriptome Analysis Reveals the Neuro-Immune Interactions in Duck Tembusu Virus-Infected Brain

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