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

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


  • Westmark CJ
  • Westmark PR
  • O'Riordan KJ
  • Ray BC
  • Hervey CM
  • Salamat MS
  • Abozeid SH
  • Stein KM
  • Stodola LA
  • Tranfaglia M
  • Burger C
  • Berry-Kravis EM
  • Malter JS


PloS one

Publication Data

November 2, 2011

Associated Grants

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

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