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

Marioly Müller, César Cárdenas, Lijuan Mei, King Ho Cheung, J. Kevin Foskett*

*Corresponding author for this work

Research output: Contribution to journalJournal articlepeer-review

75 Citations (Scopus)

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 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.

Original languageEnglish
Pages (from-to)13293-13298
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number32
Early online date22 Jul 2011
DOIs
Publication statusPublished - 9 Aug 2011

Scopus Subject Areas

  • General

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