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Article: Constitutive cAMP response element binding protein (CREB) activation by Alzheimer's disease presenilin-driven inositol trisphosphate receptor (InsP 3R) Ca 2+ signaling

TitleConstitutive cAMP response element binding protein (CREB) activation by Alzheimer's disease presenilin-driven inositol trisphosphate receptor (InsP 3R) Ca 2+ signaling
Authors
Issue Date2011
PublisherNational Academy of Sciences. The Journal's web site is located at http://www.pnas.org
Citation
Proceedings Of The National Academy Of Sciences Of The United States Of America, 2011, v. 108 n. 32, p. 13293-13298 How to Cite?
AbstractMutations in presenilins (PS) account for most early-onset familial Alzheimer's disease (FAD). Accumulating evidence suggests that disrupted Ca 2+ signaling may play a proximal role in FAD specifically, and Alzheimer's disease (AD) more generally, but its links to the pathogenesis of AD are obscure. Here we demonstrate that expression of FAD mutant PS constitutively activates the transcription factor cAMP response element binding protein (CREB) and CREB target gene expression in cultured neuronal cells and AD mouse models. Constitutive CREB activation was associated with and dependent on constitutive activation of Ca 2+/CaM kinase kinase β and CaM kinase IV (CaMKIV). Depletion of endoplasmic reticulum Ca 2+ stores or plasma membrane phosphatidylinositol-bisphosphate and pharmacologic inhibition or knockdown of the expression of the inositol trisphosphate receptor (InsP 3R) Ca 2+ release channel each abolished FAD PS-associated constitutive CaMKIV and CREB phosphorylation. CREB and CaMKIV phosphorylation and CREB target gene expression, including nitric oxide synthase and c-fos, were enhanced in brains of M146V-KI and 3xTg-AD mice expressing FAD mutant PS1 knocked into the mouse locus. FAD mutant PS-expressing cells demonstrated enhanced cell death and sensitivity to Aβ toxicity, which were normalized by interfering with the InsP 3R-CAMKIV-CREB pathway. Thus, constitutive CREB phosphorylation by exaggerated InsP 3R Ca 2+ signaling in FAD PS-expressing cells may represent a signaling pathway involved in the pathogenesis of AD.
Persistent Identifierhttp://hdl.handle.net/10722/171785
ISSN
2015 Impact Factor: 9.423
2015 SCImago Journal Rankings: 6.883
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorMüller, Men_US
dc.contributor.authorCárdenas, Cen_US
dc.contributor.authorMei, Len_US
dc.contributor.authorCheung, KHen_US
dc.contributor.authorFoskett, JKen_US
dc.date.accessioned2012-10-30T06:17:05Z-
dc.date.available2012-10-30T06:17:05Z-
dc.date.issued2011en_US
dc.identifier.citationProceedings Of The National Academy Of Sciences Of The United States Of America, 2011, v. 108 n. 32, p. 13293-13298en_US
dc.identifier.issn0027-8424en_US
dc.identifier.urihttp://hdl.handle.net/10722/171785-
dc.description.abstractMutations in presenilins (PS) account for most early-onset familial Alzheimer's disease (FAD). Accumulating evidence suggests that disrupted Ca 2+ signaling may play a proximal role in FAD specifically, and Alzheimer's disease (AD) more generally, but its links to the pathogenesis of AD are obscure. Here we demonstrate that expression of FAD mutant PS constitutively activates the transcription factor cAMP response element binding protein (CREB) and CREB target gene expression in cultured neuronal cells and AD mouse models. Constitutive CREB activation was associated with and dependent on constitutive activation of Ca 2+/CaM kinase kinase β and CaM kinase IV (CaMKIV). Depletion of endoplasmic reticulum Ca 2+ stores or plasma membrane phosphatidylinositol-bisphosphate and pharmacologic inhibition or knockdown of the expression of the inositol trisphosphate receptor (InsP 3R) Ca 2+ release channel each abolished FAD PS-associated constitutive CaMKIV and CREB phosphorylation. CREB and CaMKIV phosphorylation and CREB target gene expression, including nitric oxide synthase and c-fos, were enhanced in brains of M146V-KI and 3xTg-AD mice expressing FAD mutant PS1 knocked into the mouse locus. FAD mutant PS-expressing cells demonstrated enhanced cell death and sensitivity to Aβ toxicity, which were normalized by interfering with the InsP 3R-CAMKIV-CREB pathway. Thus, constitutive CREB phosphorylation by exaggerated InsP 3R Ca 2+ signaling in FAD PS-expressing cells may represent a signaling pathway involved in the pathogenesis of AD.en_US
dc.languageengen_US
dc.publisherNational Academy of Sciences. The Journal's web site is located at http://www.pnas.orgen_US
dc.relation.ispartofProceedings of the National Academy of Sciences of the United States of Americaen_US
dc.subject.meshAlzheimer Disease - Metabolism - Pathologyen_US
dc.subject.meshAmyloid Beta-Peptides - Toxicityen_US
dc.subject.meshAnimalsen_US
dc.subject.meshBrain - Drug Effects - Enzymology - Pathologyen_US
dc.subject.meshCalcium Signaling - Drug Effectsen_US
dc.subject.meshCalcium-Calmodulin-Dependent Protein Kinase Type 4 - Metabolismen_US
dc.subject.meshCell Death - Drug Effectsen_US
dc.subject.meshCyclic Amp Response Element-Binding Protein - Genetics - Metabolismen_US
dc.subject.meshEnzyme Activation - Drug Effectsen_US
dc.subject.meshHumansen_US
dc.subject.meshInositol 1,4,5-Trisphosphate Receptors - Metabolismen_US
dc.subject.meshMiceen_US
dc.subject.meshMice, Transgenicen_US
dc.subject.meshMutation - Geneticsen_US
dc.subject.meshPhosphorylation - Drug Effectsen_US
dc.subject.meshPresenilin-1 - Metabolismen_US
dc.subject.meshTranscription, Genetic - Drug Effectsen_US
dc.titleConstitutive cAMP response element binding protein (CREB) activation by Alzheimer's disease presenilin-driven inositol trisphosphate receptor (InsP 3R) Ca 2+ signalingen_US
dc.typeArticleen_US
dc.identifier.emailCheung, KH:kingho.cheung@hku.hken_US
dc.identifier.authorityCheung, KH=rp01463en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1073/pnas.1109297108en_US
dc.identifier.pmid21784978-
dc.identifier.scopuseid_2-s2.0-80051988063en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-80051988063&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume108en_US
dc.identifier.issue32en_US
dc.identifier.spage13293en_US
dc.identifier.epage13298en_US
dc.identifier.isiWOS:000293691400066-
dc.publisher.placeUnited Statesen_US
dc.identifier.scopusauthoridMüller, M=7404689330en_US
dc.identifier.scopusauthoridCárdenas, C=7003841618en_US
dc.identifier.scopusauthoridMei, L=7103211483en_US
dc.identifier.scopusauthoridCheung, KH=14007487800en_US
dc.identifier.scopusauthoridFoskett, JK=7005723620en_US
dc.identifier.citeulike9588350-

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