Journal
PLOS ONE
Volume 6, Issue 10, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0026549
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Funding
- FRAXA Research Foundation
- Illinois-Eastern Iowa Kiwanis Spastic Paralysis and Related Disorders Foundation
- National Institutes of Health [P30 HD03352, R01DA026067]
- University of WI
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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 beta-protein precursor (A beta PP) mRNA. Cleavage of A beta PP can produce beta-amyloid (A beta), a 39-43 amino acid peptide mis-expressed in Alzheimer's disease (AD) and Down syndrome (DS). A beta is over-expressed in the brain of Fmr1(KO) mice, suggesting a pathogenic role in FXS. To determine if genetic reduction of A beta PP/A beta 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 A beta(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 A beta is sequestered in the brain. Evolving therapies directed at reducing A beta in AD may be applicable to FXS and A beta may serve as a plasma-based biomarker to facilitate disease diagnosis or assess therapeutic efficacy.
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