Linked Life Data

21784978

Source:http://linkedlifedata.com/resource/pubmed/id/21784978

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
32
pubmed:dateCreated
2011-8-11
pubmed:abstractText
Mutations 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 ? 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(3)R) 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 A? toxicity, which were normalized by interfering with the InsP(3)R-CAMKIV-CREB pathway. Thus, constitutive CREB phosphorylation by exaggerated InsP(3)R Ca(2+) signaling in FAD PS-expressing cells may represent a signaling pathway involved in the pathogenesis of AD.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Aug
pubmed:issn
1091-6490
pubmed:author
pubmed:issnType
Electronic
pubmed:day
9
pubmed:volume
108
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
13293-8
pubmed:meshHeading
pubmed-meshheading:21784978-Alzheimer Disease, pubmed-meshheading:21784978-Amyloid beta-Peptides, pubmed-meshheading:21784978-Animals, pubmed-meshheading:21784978-Brain, pubmed-meshheading:21784978-Calcium Signaling, pubmed-meshheading:21784978-Calcium-Calmodulin-Dependent Protein Kinase Type 4, pubmed-meshheading:21784978-Cell Death, pubmed-meshheading:21784978-Cyclic AMP Response Element-Binding Protein, pubmed-meshheading:21784978-Enzyme Activation, pubmed-meshheading:21784978-Humans, pubmed-meshheading:21784978-Inositol 1,4,5-Trisphosphate Receptors, pubmed-meshheading:21784978-Mice, pubmed-meshheading:21784978-Mice, Transgenic, pubmed-meshheading:21784978-Mutation, pubmed-meshheading:21784978-Phosphorylation, pubmed-meshheading:21784978-Presenilin-1, pubmed-meshheading:21784978-Transcription, Genetic
pubmed:year
2011
pubmed:articleTitle
Constitutive cAMP response element binding protein (CREB) activation by Alzheimer's disease presenilin-driven inositol trisphosphate receptor (InsP3R) Ca2+ signaling.
pubmed:affiliation
Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural