Reversal of fragile X phenotypes by manipulation of AβPP/Aβ levels in Fmr1KO mice
| Autor: | Elizabeth Berry-Kravis, Sara Abozeid, Crystal Hervey, M. Shahriar Salamat, Brian C. Ray, James S. Malter, Corinna Burger, Cara J. Westmark, Pamela R. Westmark, Kenneth J. O’Riordan, Kelsey M. Stein, Levi A. Stodola, Michael Tranfaglia |
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| Rok vydání: | 2011 |
| Předmět: |
Male
Dendritic spine Mouse lcsh:Medicine Hippocampal formation Developmental and Pediatric Neurology Receptors Metabotropic Glutamate Pediatrics Amyloid beta-Protein Precursor Fragile X Mental Retardation Protein Mice Behavioral Neuroscience 0302 clinical medicine Neurobiology of Disease and Regeneration lcsh:Science Receptor Mice Knockout Neurons 0303 health sciences Multidisciplinary Neuronal Morphology Cognitive Neurology Animal Models Fragile X syndrome Phenotype Neurology Medicine Female Research Article medicine.medical_specialty Down syndrome congenital hereditary and neonatal diseases and abnormalities Drugs and Devices Drug Research and Development Dendritic Spines Down-Regulation Biology Signaling Pathways 03 medical and health sciences Model Organisms Internal medicine medicine Animals Allele 030304 developmental biology Brain Chemistry Amyloid beta-Peptides lcsh:R Genetic Therapy medicine.disease FMR1 Peptide Fragments Endocrinology Metabotropic glutamate receptor Fragile X Syndrome Cellular Neuroscience Immunology lcsh:Q Molecular Neuroscience 030217 neurology & neurosurgery Neuroscience |
| Zdroj: | PLoS ONE PLoS ONE, Vol 6, Iss 10, p e26549 (2011) |
| ISSN: | 1932-6203 |
| Popis: | Fragile X syndrome (FXS) is the most common form of inherited intellectual disability and the leading known genetic cause of autism. Fragile X mental retardation protein (FMRP), which is absent or expressed at substantially reduced levels in FXS, binds to and controls the postsynaptic translation of amyloid β-protein precursor (AβPP) mRNA. Cleavage of AβPP can produce β-amyloid (Aβ), a 39-43 amino acid peptide mis-expressed in Alzheimer's disease (AD) and Down syndrome (DS). Aβ is over-expressed in the brain of Fmr1(KO) mice, suggesting a pathogenic role in FXS. To determine if genetic reduction of AβPP/Aβ rescues characteristic FXS phenotypes, we assessed audiogenic seizures (AGS), anxiety, the ratio of mature versus immature dendritic spines and metabotropic glutamate receptor (mGluR)-mediated long-term depression (LTD) in Fmr1(KO) mice after removal of one App allele. All of these phenotypes were partially or completely reverted to normal. Plasma Aβ(1-42) was significantly reduced in full-mutation FXS males compared to age-matched controls while cortical and hippocampal levels were somewhat increased, suggesting that Aβ is sequestered in the brain. Evolving therapies directed at reducing Aβ in AD may be applicable to FXS and Aβ may serve as a plasma-based biomarker to facilitate disease diagnosis or assess therapeutic efficacy. |
| Databáze: | OpenAIRE |
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