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Reversal of fragile X phenotypes by manipulation of AβPP/Aβ levels in Fmr1KO mice.

PloS one | Nov 2, 2011

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.

Pubmed ID: 22046307 RIS Download

Mesh terms: Amyloid beta-Peptides | Amyloid beta-Protein Precursor | Animals | Brain Chemistry | Dendritic Spines | Down-Regulation | Female | Fragile X Mental Retardation Protein | Fragile X Syndrome | Genetic Therapy | Male | Mice | Mice, Knockout | Neurons | Peptide Fragments | Phenotype | Receptors, Metabotropic Glutamate

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Associated grants

  • Agency: NICHD NIH HHS, Id: P30 HD003352
  • Agency: NIDA NIH HHS, Id: R01 DA026067
  • Agency: NICHD NIH HHS, Id: P30 HD03352
  • Agency: NIDA NIH HHS, Id: R01DA026067

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FRAXA Research Foundation

FRAXA's mission is to accelerate progress toward effective treatments and ultimately a cure for Fragile X, by directly funding the most promising research. FRAXA also supports families affected by Fragile X and raises awareness of this important but relatively unknown disease. FRAXA was founded in 1994 by three parents of children with Fragile X, Katie Clapp, Michael Tranfaglia MD, and Kathy May, to support scientific research aimed at finding a treatment and a cure for Fragile X. Fragile X research is drastically underfunded, considering its high prevalence, prospects for a cure, and the promise that this research holds for advancing understanding of other disorders like autism, Alzheimer's disease, and X-linked mental retardation. FRAXA funds grants and fellowships at universities all over the world. We have funded more than $17 million dollars in top-notch science. FRAXA's management expenses have always been just 4% or less of income, as we have just one full-time staff, three part time staff, and hundreds of volunteer parents. Since FRAXA was founded, the Fragile X field has grown tremendously, due in large part to our grass-roots efforts. You can help us accomplish much more. FRAXA is a 501c3 tax-exempt organization; Tax ID 04-3222167

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