Reversal of fragile X phenotypes by manipulation of AβPP/Aβ levels in Fmr1 KO 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, James S. Malter

Research output: Contribution to journalArticlepeer-review

100 Scopus citations

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.

Original languageEnglish (US)
Article numbere26549
JournalPloS one
Volume6
Issue number10
DOIs
StatePublished - 2011

ASJC Scopus subject areas

  • General Biochemistry, Genetics and Molecular Biology
  • General Agricultural and Biological Sciences
  • General

Fingerprint

Dive into the research topics of 'Reversal of fragile X phenotypes by manipulation of AβPP/Aβ levels in Fmr1 KO mice'. Together they form a unique fingerprint.

Cite this