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 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 Fmr1(KO) 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 Fmr1(KO) mice after removal of one App allele. All of these phenotypes were partially or completely reverted to normal. Plasma Aß(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 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.