Fragile X mental retardation protein (FMRP), which is absent or expressed at substantially reduced levels in Fragile X syndrome, binds to and controls the postsynaptic translation of several mRNAs including amyloid b-protein precursor (APP) mRNA. Cleavage of APP produces b-amyloid (Ab), a peptide over-expressed in Alzheimer’s disease (AD) and Down syndrome (DS).
Ab is over-expressed in the brains of FXS mice (Fmr1 KO), suggesting a pathogenic role in FXS. Consistent with this hypothesis, characteristic Fmr1 KO phenotypes are partially or completely reverted to normal in Fmr1 KO mice after removal of one AbPP allele.
The mechanism by which APP/Ab contribute to FXS is unknown. We have found that Ab increases new dendritic protein synthesis of several proteins known to be regulated by FMRP including APP. These data suggest a positive feedback cycle by which Ab allows itself to be maintained at damaging levels.
Our experiments address two critical gaps in this mechanism: (1) is there excessive Ab-mediated mGluR5 signaling in Fmr1 KO cells, and (2) can a BACE-1 inhibitor be employed to reduce Ab levels and block this positive feedback loop. Secretase inhibitors are under intense investigation for the treatment of AD with g-secretase inhibitors currently in clinical trials. Positive results from this study would support testing secretase inhibitors in FXS.
Dr. Westmark continues to study APP which is regulated by FMRP and, therefore, overexpressed in FX. AßPP is cleaved by ß-secretase (BACE-1) to form Aß which is also overabundant in FX (as well as Alzheimer’s and Down syndrome). Aß stimulates the mGluR5 pathway and FMRP signaling, causing more AßPP and BACE-1 processing and, therefore, more Aß production, resulting in an endless loop of stimulation.
Dr. Westmark is conducting studies to see if inhibition of BACE-1 could rescue overexpression of FMRP targets and/or mGLuR-long term depression seen in FX. To date her project has made some exciting findings in this area and continues to look at this pathway which could lead to therapeutics for FX as well as Alzheimer’s and Down syndrome.