Journal article
Suppression of InsP3 receptor-mediated Ca2+ signaling alleviates mutant presenilin-linked familial Alzheimer's disease pathogenesis
The Journal of neuroscience, Vol.34(20), pp.6910-6923
05/14/2014
DOI: 10.1523/JNEUROSCI.5441-13.2014
PMCID: PMC4019804
PMID: 24828645
Abstract
Exaggerated intracellular Ca(2+) signaling is a robust proximal phenotype observed in cells expressing familial Alzheimer's disease (FAD)-causing mutant presenilins (PSs). The mechanisms that underlie this phenotype are controversial and their in vivo relevance for AD pathogenesis is unknown. Here, we used a genetic approach to identify the mechanisms involved and to evaluate their role in the etiology of AD in two FAD mouse models. Genetic reduction of the type 1 inositol trisphosphate receptor (InsP3R1) by 50% normalized exaggerated Ca(2+) signaling observed in cortical and hippocampal neurons in both animal models. In PS1M146V knock-in mice, reduced InsP3R1 expression restored normal ryanodine receptor and cAMP response element-binding protein (CREB)-dependent gene expression and rescued aberrant hippocampal long-term potentiation (LTP). In 3xTg mice, reduced InsP3R1 expression profoundly attenuated amyloid β accumulation and tau hyperphosphorylation and rescued hippocampal LTP and memory deficits. These results indicate that exaggerated Ca(2+) signaling, which is associated with FAD PS, is mediated by InsP3R and contributes to disease pathogenesis in vivo. Targeting the InsP3 signaling pathway could be considered a potential therapeutic strategy for patients harboring mutations in PS linked to AD.
Details
- Title: Subtitle
- Suppression of InsP3 receptor-mediated Ca2+ signaling alleviates mutant presenilin-linked familial Alzheimer's disease pathogenesis
- Creators
- Dustin Shilling - Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104Marioly Müller - Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104Hajime Takano - Departments of Pediatrics, Neurology, and Neuroscience, Perelman School of Medicine, University of Pennsylvania and the Division of Neurology and the Pediatric Regional Epilepsy Program, the Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104Don-On Daniel Mak - Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104Ted Abel - Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, andDouglas A Coulter - Departments of Pediatrics, Neurology, and Neuroscience, Perelman School of Medicine, University of Pennsylvania and the Division of Neurology and the Pediatric Regional Epilepsy Program, the Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104J Kevin Foskett - Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104 foskett@mail.med.upenn.edu
- Resource Type
- Journal article
- Publication Details
- The Journal of neuroscience, Vol.34(20), pp.6910-6923
- Publisher
- United States
- DOI
- 10.1523/JNEUROSCI.5441-13.2014
- PMID
- 24828645
- PMCID
- PMC4019804
- ISSN
- 0270-6474
- eISSN
- 1529-2401
- Grant note
- R01 MH059937 / NIMH NIH HHS MH059937 / NIMH NIH HHS AG038240 / NIA NIH HHS F31 AG038240 / NIA NIH HHS
- Language
- English
- Date published
- 05/14/2014
- Academic Unit
- Molecular Physiology and Biophysics; Psychiatry; Psychological and Brain Sciences; Iowa Neuroscience Institute; Neuroscience and Pharmacology; Biochemistry and Molecular Biology
- Record Identifier
- 9984065832202771
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