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

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dc.contributor.authorCisternas, Pedro
dc.contributor.authorZolezzi, Juan M.
dc.contributor.authorMartinez, Milka
dc.contributor.authorTorres, Viviana I.
dc.contributor.authorWong, Guang William
dc.contributor.authorInestrosa, Nibaldo C.
dc.date.accessioned2024-01-10T12:11:02Z
dc.date.available2024-01-10T12:11:02Z
dc.date.issued2019
dc.description.abstractDysregulated 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.
dc.description.funderBasal Center of Excellence in Aging and Regeneration
dc.description.funderFONDECYT
dc.description.funderNational Institute of Health
dc.description.funderSociedad Quimica y Minera de Chile (SQM)
dc.description.funderNATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
dc.fechaingreso.objetodigital2024-05-14
dc.format.extent19 páginas
dc.fuente.origenWOS
dc.identifier.doi10.1111/jnc.14608
dc.identifier.eissn1471-4159
dc.identifier.issn0022-3042
dc.identifier.pubmedidMEDLINE:30300917
dc.identifier.urihttps://doi.org/10.1111/jnc.14608
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/76625
dc.identifier.wosidWOS:000462680200005
dc.information.autorucCiencias Biológicas;Cisternas P, Zolezzi JM, Marti;S/I;99331
dc.issue.numero1
dc.language.isoen
dc.nota.accesocontenido parcial
dc.pagina.final72
dc.pagina.inicio54
dc.publisherWILEY
dc.revistaJOURNAL OF NEUROCHEMISTRY
dc.rightsacceso restringido
dc.subjectAlzheimer disease
dc.subjectglucose metabolism
dc.subjectneuroprotection
dc.subjectWnt signaling
dc.subjectINTRANASAL INSULIN
dc.subjectCOGNITIVE PERFORMANCE
dc.subjectTRANSPORTER GLUT1
dc.subjectBRAIN
dc.subjectNEURONS
dc.subjectMODEL
dc.subjectMICE
dc.subjectMITOCHONDRIA
dc.subjectIMPAIRMENT
dc.subjectCATENIN
dc.subject.ods03 Good Health and Well-being
dc.subject.odspa03 Salud y bienestar
dc.titleWnt-induced activation of glucose metabolism mediates the in vivo neuroprotective roles of Wnt signaling in Alzheimer disease
dc.typeartículo
dc.volumen149
sipa.codpersvinculados99331
sipa.indexWOS
sipa.indexScopus
sipa.trazabilidadCarga SIPA;09-01-2024
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