James Malter

James Malter, PhD
Principal Investigator
Cara J. Westmark, PhD
Assistant Investigator
University of Wisconsin-Madison

FRAXA Awards:
  $60,000 in 2009 
  $60,000 in 2008 
  $10,000 in 2008

Utilization of Fenobam to Reduce APP and Abeta in Fragile X Mice

By James Malter and Cara Westmark, 5/2008

We have identified amyloid precursor protein (APP) mRNA as a synaptic target of fragile X mental retardation protein (FMRP). APP is the parent molecule, which is cleaved to form beta-amyloid (A), the predominant protein found in the senile plaques in Alzheimer’s disease. APP presents a conundrum in that it is required early in development for synaptogenesis, yet, excessive cleavage to Ab in Alzheimer’s disease and Down syndrome contributes to neurodegeneration. We have demonstrated a significant increase in APP levels in the dendrites of neuronal cells prepared from embryonic fragile X mice as well as increased Ab levels in whole brain lysates prepared from middle-aged fragile X mice. Thus, over-expression of APP early in development could play an important role in the abnormal dendritic spine morphology characteristic of fragile X syndrome, and increased Ab load with aging could contribute to the maintenance of cognitive impairment.

FMRP binds to and represses the synthesis of APP via an mGluR₅-dependent signaling pathway. We are treating fragile X mice with the mGluR₅ inhibitor, fenobam, as a food additive with the goal of reducing APP and Ablevels and attenuating downstream pathology and behavioral deficits. Preliminary data has demonstrated significant reductions in brain Ablevels with chronic fenobam treatment over a one-month period. Our goal in this FRAXA-sponsored research is to correlate fenobam-mediated reductions in APP and/or Ab with improved cognitive abilities and attenuated seizure phenotypes in fragile X mice. Audiogenic seizures are a prevalent phenotype in fragile X syndrome, and we have observed an increased propensity for both chemically induced and audiogenic seizures in multiple mouse models of Alzheimer’s disease. We believe that over-production of APP or a proteolytic product of APP is responsible for seizure induction in both disorders. We have attenuated seizures in the Alzheimer’s mice chemically through mGluR₅ blockade and in fragile X mice genetically by hemizygous knockout of the APP gene.