Constitutive cAMP response element binding protein (CREB) activation by Alzheimer's disease presenilin-driven inositol trisphosphate receptor (InsP 3 R) Ca 2+ signaling
- 22 July 2011
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 108 (32), 13293-13298
- https://doi.org/10.1073/pnas.1109297108
Abstract
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 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(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 Aβ 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.Keywords
This publication has 66 references indexed in Scilit:
- CBP gene transfer increases BDNF levels and ameliorates learning and memory deficits in a mouse model of Alzheimer's diseaseProceedings of the National Academy of Sciences, 2010
- Essential Regulation of Cell Bioenergetics by Constitutive InsP3 Receptor Ca2+ Transfer to MitochondriaCell, 2010
- Alzheimer’s Disease and Neuronal Network ActivityNeuroMolecular Medicine, 2009
- Amyloid-beta Leads to Impaired Cellular Respiration, Energy Production and Mitochondrial Electron Chain Complex Activities in Human Neuroblastoma CellsCellular and Molecular Neurobiology, 2009
- Neuronal calcium mishandling and the pathogenesis of Alzheimer's diseaseTrends in Neurosciences, 2008
- SERCA pump activity is physiologically regulated by presenilin and regulates amyloid β productionThe Journal of cell biology, 2008
- Mechanism of Ca2+ Disruption in Alzheimer's Disease by Presenilin Regulation of InsP3 Receptor Channel GatingNeuron, 2008
- Regulation of cyclic AMP response-element binding-protein (CREB) by Gq/11-protein-coupled receptors in human SH-SY5Y neuroblastoma cellsBiochemical Pharmacology, 2008
- CaMKII and CaMKIV mediate distinct prosurvival signaling pathways in response to depolarization in neuronsMolecular and Cellular Neuroscience, 2007
- Pathways towards and away from Alzheimer's diseaseNature, 2004