| First Author | Westmark CJ | Year | 2011 |
| Journal | PLoS One | Volume | 6 |
| Issue | 10 | Pages | e26549 |
| PubMed ID | 22046307 | Mgi Jnum | J:178076 |
| Mgi Id | MGI:5297269 | Doi | 10.1371/journal.pone.0026549 |
| Citation | Westmark CJ, et al. (2011) Reversal of Fragile X Phenotypes by Manipulation of AbetaPP/Abeta Levels in Fmr1 Mice. PLoS One 6(10):e26549 |
| abstractText | 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 beta-protein precursor (AbetaPP) mRNA. Cleavage of AbetaPP can produce beta-amyloid (Abeta), a 39-43 amino acid peptide mis-expressed in Alzheimer's disease (AD) and Down syndrome (DS). Abeta is over-expressed in the brain of Fmr1(KO) mice, suggesting a pathogenic role in FXS. To determine if genetic reduction of AbetaPP/Abeta 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 Abeta(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 Abeta is sequestered in the brain. Evolving therapies directed at reducing Abeta in AD may be applicable to FXS and Abeta may serve as a plasma-based biomarker to facilitate disease diagnosis or assess therapeutic efficacy. |
