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.
Subject(s)
Amyloid beta-Peptides/metabolism , Amyloid beta-Protein Precursor/metabolism , Fragile X Mental Retardation Protein/genetics , Fragile X Syndrome/prevention & control , Fragile X Syndrome/therapy , Peptide Fragments/metabolism , Amyloid beta-Peptides/blood , Amyloid beta-Peptides/genetics , Amyloid beta-Protein Precursor/blood , Amyloid beta-Protein Precursor/genetics , Animals , Brain Chemistry , Dendritic Spines , Down-Regulation , Female , Fragile X Mental Retardation Protein/metabolism , Fragile X Syndrome/genetics , Fragile X Syndrome/metabolism , Genetic Therapy , Male , Mice , Mice, Knockout , Neurons/ultrastructure , Peptide Fragments/blood , Peptide Fragments/genetics , Phenotype , Receptors, Metabotropic Glutamate/geneticsABSTRACT
Altered levels of amyloid ß-protein precursor (AßPP) and/or amyloid beta (Aß) are characteristic of several neurological disorders including Alzheimer's disease (AD), Down syndrome (DS), Fragile X syndrome (FXS), Parkinson's disease (PD), autism and epilepsy. Thus, these proteins could serve as valuable blood-based biomarkers for assessing disease severity and pharmacological efficacy. We have observed significant differences in Aß1-42 levels in human plasma dependent on the anticoagulant utilized during blood collection. Our data suggests that anticoagulants alter AßPP processing and that care needs to be used in comparing published studies that have not utilized the same blood collection methodology.
