Title |
Reversal of Fragile X Phenotypes by Manipulation of AβPP/Aβ Levels in Fmr1KO Mice
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Published in |
PLOS ONE, October 2011
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DOI | 10.1371/journal.pone.0026549 |
Pubmed ID | |
Authors |
Cara J. Westmark, Pamela R. Westmark, Kenneth J. O'Riordan, Brian C. Ray, Crystal M. Hervey, M. Shahriar Salamat, Sara H. Abozeid, Kelsey M. Stein, Levi A. Stodola, Michael Tranfaglia, Corinna Burger, Elizabeth M. Berry-Kravis, James S. Malter |
Abstract |
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. |
X Demographics
Geographical breakdown
Country | Count | As % |
---|---|---|
Unknown | 1 | 100% |
Demographic breakdown
Type | Count | As % |
---|---|---|
Members of the public | 1 | 100% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
United Kingdom | 2 | 1% |
Chile | 1 | <1% |
Netherlands | 1 | <1% |
France | 1 | <1% |
Canada | 1 | <1% |
Unknown | 128 | 96% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Student > Ph. D. Student | 27 | 20% |
Researcher | 25 | 19% |
Student > Bachelor | 18 | 13% |
Student > Master | 13 | 10% |
Student > Doctoral Student | 9 | 7% |
Other | 20 | 15% |
Unknown | 22 | 16% |
Readers by discipline | Count | As % |
---|---|---|
Agricultural and Biological Sciences | 44 | 33% |
Neuroscience | 24 | 18% |
Medicine and Dentistry | 16 | 12% |
Psychology | 15 | 11% |
Biochemistry, Genetics and Molecular Biology | 11 | 8% |
Other | 4 | 3% |
Unknown | 20 | 15% |