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Neurological Disorders - Neuroscience - Pediatrics and Child Health - Pharmacology

Reversal of Fragile X Phenotypes by Manipulation of AßPP/Aß Levels in Fmr1KO Mice
Published: Wednesday, October 26, 2011
Author: Cara J. Westmark et al.

by 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

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 ß-protein precursor (AßPP) mRNA. Cleavage of AßPP can produce ß-amyloid (Aß), a 39–43 amino acid peptide mis-expressed in Alzheimer's disease (AD) and Down syndrome (DS). Aß is over-expressed in the brain of Fmr1KO mice, suggesting a pathogenic role in FXS. To determine if genetic reduction of AßPP/Aß 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 Aß1–42 was significantly reduced in full-mutation FXS males compared to age-matched controls while cortical and hippocampal levels were somewhat increased, suggesting that Aß is sequestered in the brain. Evolving therapies directed at reducing Aß in AD may be applicable to FXS and Aß may serve as a plasma-based biomarker to facilitate disease diagnosis or assess therapeutic efficacy.