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dc.contributor.authorStygelbout, Virginie
dc.contributor.authorLeroy, Karelle
dc.contributor.authorPouillon, Valerie
dc.contributor.authorAndo, Kunie
dc.contributor.authorD’Amico, Eva
dc.contributor.authorJia, Yonghui
dc.contributor.authorLuo, Hongbo
dc.contributor.authorDuyckaerts, Charles
dc.contributor.authorErneux, Christophe
dc.contributor.authorSchurmans, Stephane
dc.contributor.authorBrion, Jean-Pierre
dc.date.accessioned2014-11-05T21:02:15Z
dc.date.issued2014
dc.identifier.citationStygelbout, Virginie, Karelle Leroy, Valerie Pouillon, Kunie Ando, Eva D’Amico, Yonghui Jia, Hongbo Robert Luo, et al. 2014. “Inositol Trisphosphate 3-Kinase B Is Increased in Human Alzheimer Brain and Exacerbates Mouse Alzheimer Pathology.” Brain 137 (2) (January 8): 537–552. doi:10.1093/brain/awt344. http://dx.doi.org/10.1093/brain/awt344.en_US
dc.identifier.issn0006-8950en_US
dc.identifier.issn1460-2156en_US
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:13350301
dc.description.abstractITPKB phosphorylates inositol 1,4,5-trisphosphate into inositol 1,3,4,5-tetrakisphosphate and controls signal transduction in various hematopoietic cells. Surprisingly, it has been reported that the ITPKB messenger RNA level is significantly increased in the cerebral cortex of patients with Alzheimer’s disease, compared with control subjects. As extracellular signal-regulated kinases 1/2 activation is increased in the Alzheimer brain and as ITPKB is a regulator of extracellular signal-regulated kinases 1/2 activation in some hematopoietic cells, we tested whether this increased activation in Alzheimer’s disease might be related to an increased activity of ITPKB. We show here that ITPKB protein level was increased 3-fold in the cerebral cortex of most patients with Alzheimer’s disease compared with control subjects, and accumulated in dystrophic neurites associated to amyloid plaques. In mouse Neuro-2a neuroblastoma cells, Itpkb overexpression was associated with increased cell apoptosis and increased β-secretase 1 activity leading to overproduction of amyloid-β peptides. In this cellular model, an inhibitor of mitogen-activated kinase kinases 1/2 completely prevented overproduction of amyloid-β peptides. Transgenic overexpression of ITPKB in mouse forebrain neurons was not sufficient to induce amyloid plaque formation or tau hyperphosphorylation. However, in the 5X familial Alzheimer’s disease mouse model, neuronal ITPKB overexpression significantly increased extracellular signal-regulated kinases 1/2 activation and β-secretase 1 activity, resulting in exacerbated Alzheimer’s disease pathology as shown by increased astrogliosis, amyloid-\(β_{40}\) peptide production and tau hyperphosphorylation. No impact on pathology was observed in the 5X familial Alzheimer’s disease mouse model when a catalytically inactive ITPKB protein was overexpressed. Together, our results point to the ITPKB/inositol 1,3,4,5-tetrakisphosphate/extracellular signal-regulated kinases 1/2 signalling pathway as an important regulator of neuronal cell apoptosis, APP processing and tau phosphorylation in Alzheimer’s disease, and suggest that ITPKB could represent a new target for reducing pathology in human patients with Alzheimer’s disease with ITPKB expression.en_US
dc.language.isoen_USen_US
dc.publisherOxford University Press (OUP)en_US
dc.relation.isversionofdoi:10.1093/brain/awt344en_US
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pubmed/24401760en_US
dash.licenseMETA_ONLY
dc.subjectAlzheimer pathologyen_US
dc.subjectinositol phosphatesen_US
dc.subjectITPKBen_US
dc.subjectinositol (1,3,4,5) tetrakisphosphateen_US
dc.titleInositol Trisphosphate 3-Kinase B Is Increased in Human Alzheimer Brain and Exacerbates Mouse Alzheimer Pathologyen_US
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden_US
dc.relation.journalBrainen_US
dash.depositing.authorLuo, Hongbo
dash.embargo.until10000-01-01
dc.identifier.doi10.1093/brain/awt344*
workflow.legacycommentsDeposit dark per Luoen_US
dash.authorsorderedfalse
dash.contributor.affiliatedLuo, Hongbo


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