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

• Published in: Journal of neurochemistry 2019-04, Vol.149 (1), p.54-72
• Main Authors: Cisternas, Pedro, Zolezzi, Juan M., Martinez, Milka, Torres, Viviana I., Wong, Guang William, Inestrosa, Nibaldo C.
• Format: Article
• Language: English
• Subjects: Activation; Adenosine diphosphate; Adenosine triphosphate; Alzheimer disease; Alzheimer Disease - metabolism; Alzheimer's disease; AMP; Animal models; Animals; ATP; Brain; Brain - metabolism; Brain slice preparation; Cognitive ability; Cortex; Cytochalasin B; Embryos; Glucose; Glucose - metabolism; Glucosephosphate dehydrogenase; Glycolysis; Hexokinase; Hippocampus; Humans; In vivo methods and tests; Kinases; Learning; Lithium; Memory; Metabolism; Mice; Mice, Transgenic; Neurodegenerative diseases; Neurological diseases; Neurons; Neuroprotection; Object recognition; Pattern recognition; Pentose; Pentose phosphate pathway; Phosphates; Phosphofructokinase; Protein kinase; Proteins; Radioactive tracers; Rats; Rodents; Signal transduction; Signaling; Transgenic mice; Wnt signaling; Wnt Signaling Pathway - physiology
• ISSN: 0022-3042; 1471-4159; 1471-4159
• DOI: 10.1111/jnc.14608

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. Dysregulated Wnt signaling is linked to major neurodegenerative diseases, including Alzheimer disease (AD). 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. Wnt activators significantly improved brain glucose utilization and cognitive performance in transgenic mice. The neuroprotective effects of Wnt signaling in AD mouse models result, at least in part, from Wnt‐mediated improvements in neuronal glucose metabolism.