Reversal of Fragile X Phenotypes by Manipulation of AβPP/Aβ Levels in Fmr1KO Mice

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 and James S Malter

PLOS ONE, 2011, vol. 6, issue 10, 1-11

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 Fmr1KO 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 Fmr1KO mice after removal of one App allele. All of these phenotypes were partially or completely reverted to normal. Plasma Aβ1–42 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.

Date: 2011
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Persistent link: https://EconPapers.repec.org/RePEc:plo:pone00:0026549

DOI: 10.1371/journal.pone.0026549

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