Cara J. Westmark
PhD, University of Notre Dame
Senior Scientist, Pathology & Laboratory Medicine

Contact Information:
Waisman Center
UW-Madison
1500 Highland Avenue
Madison, WI 53705
Phone: (608) 262-9730
Email: westmark@wisc.edu

Research Statement

I am investigating the role of amyloid precursor protein (APP) in Alzheimer’s disease (AD), Down syndrome (DS) and Fragile X syndrome (FXS). APP is the parent molecule that is cleaved by secretases to produce beta2-amyloid, which is the predominant protein found in senile plaques in the brains of AD and DS individuals. The normal physiological function of APP is not well defined, but it is expressed at synapses where it promotes synapse differentiation during development. APP exhibits increased expression during neuronal differentiation with maximal levels at the time of synaptic connection completion. Of note, the role of synaptic dysfunction has received increasing attention as a primary upstream lesion in early AD. Thus, APP facilitates synapse formation in the developing brain, while beta2-amyloid accumulation results in synaptic loss and impaired neurotransmission.

I have found that APP is regulated at the protein synthesis level by fragile X mental retardation protein (FMRP), an RNA binding protein that is absent in individuals with FXS. FXS occurs because the mutated fmr-1 gene does not produce enough FMRP, which is needed for normal dendritic spine development. FMRP is a multi-functional mRNA binding protein involved in the transport, localization and translational regulation of mRNA ligands. In neurons, FMRP is located in polysomes and in nontranslating ribonucleoprotein (RNP) particles of dendrites. The RNPs contain the FMRP homologs FXR1 and 2, the guide RNA BC1 and other proteins and mRNAs involved in synaptic plasticity. Hundreds of mRNA ligands have been identified with many found at synapses and having the potential to influence synapse formation and synaptic plasticity. It has been proposed that FMRP is an “immediate early protein” at the synapse orchestrating synaptic development and plasticity.

I have shown that APP and beta2-amyloid levels are dysregulated in a mouse model of FXS as well as in human FXS blood plasma and brain samples suggesting that APP and beta2-amyloid are possible biomarkers for FXS. My data demonstrates that postsynaptic FMRP binds to and regulates the translation of APP mRNA through group 1 mGluR activation, which suggests that APP and beta2-amyloid levels could be controlled with drugs that specifically block this membrane receptor. I am currently treating AD, DS and FXS mouse models with mGluR5 inhibitors and assessing their effects on beta2-amyloid levels, behavior and memory.

Representative Publications

Cara J. Westmark and James S. Malter. “Translating Memories: The Role of Protein Biosynthesis in Synaptic Plasticity.” Nova book chapter. In press.

Cara J. Westmark, Pamela R. Westmark, Ashley M. Beard, Sharon M. Hildebrandt and James S. Malter. (2008). Seizure Susceptibility and Mortality in Mice that Over-Express Amyloid Precursor Protein.International journal of clinical and experimental pathology 1, 157-68.

Stephane J. Esnault, Lou A. Rosenthal, Zong Z. J. Shen, Ronald L. Sorkness and James S. Malter.(2008) Thymic Stromal Lymphopoietin Expression in Allergic Pulmonary Inflammation is Pin1-Dependent. Journal of Allergy and Clinical Immunology 121, 1289-90.

Cara J. Westmark and James S. Malter.(2007) FMRP Mediates mGluR5-Dependent Translation of Amyloid Precursor Protein. PLOS Biology 5, e52.

Pamela R. Westmark, Hyun C. Shin, Cara J. Westmark, Syrus Soltanissab, Emily Reinke and James S. Malter.(2006) Decoy mRNAs Reduce beta2-Amyloid Precursor Protein mRNA in Neuronal Cells. Neurobiology of Aging 27, 787-96.

Cara J. Westmark, Franoise A. Gourronc, Virginia B. Bartleson, Umit Sayin, Saswati Bhattacharya, Tom Sutula and James S. Malter.(2005) HuR mRNA Ligands Expressed After Seizure. Journal of Neuropathology and Experimental Neurology 64, 1037-45.

Cara J. Westmark, Virginia B. Bartleson and James S. Malter.(2005). RhoB mRNA is Stabilized by HuR After UVL. Oncogene 24, 502-511.

Cara J. Westmark, Romi Ghose and Paul W. Huber. (2002).Phosphorylation of Xenopus Transcription Factor IIIA by an Oocyte Protein Kinase CK2. Biochemistry Journal 362, 375-82.

Cara J. Westmark and James S. Malter. (2001). Extracellular-Regulated Kinase Controls Beta-Amyloid Precursor Protein mRNA Decay. Brain Research Molecular Brain Research 90, 193-201.

Cara J. Westmark and James S. Malter. (2001). Up-Regulation of Nucleolin mRNA and Protein in Peripheral Blood Mononuclear Cells by Extracellular-Regulated Kinase. Journal of Biological Chemistry 276, 1119-26.

Cara J. Westmark, Romi Ghose and Paul W. Huber. (1998). Inhibition of RNA Polymerase III Transcription by a Ribosome-Associated Kinase Activity. Nucleic Acids Research 26, 4758-4764.

Lakshman E. Rajagopalan, Cara J. Westmark, Jason A. Jarzembowski and James S. Malter. (1998). hnRNP C Increases Amyloid Precursor Protein (APP) Production by Stabilizing APP mRNA. Nucleic Acids Research 26, 3418-3423.