Cerebrovascular pathology in Alzheimer’s disease and related disorders

Ph.D., Biochemistry, University of California, 1985

We are interested in understanding the role of amyloid ß-protein precursor (AßPP) and its derived fragment Aß in the cerebrovascular pathology found in Alzheimer’s disease and related disorders. Our research focuses on pathogenic interactions of Aß with cells in cerebral blood vessels that lead to cellular degeneration, loss of vessel wall integrity, and hemorrhagic stroke. Our studies in this area are multi-leveled involving basic protein-protein interactions, in vitro cerebrovascular cell culture models, and several in vivo transgenic mouse models recently developed in the laboratory. In addition, we have a strong interest in physiologic functions of AßPP in regulating hemostatic mechanisms. To this end we utilize in vitro systems and several in vivo mouse gene knockout and transgenic models to elucidate the role of AßPP in vascular processes involved in coagulation, stroke, and traumatic brain injury.

Selected Publications

• Melchor, J.P. and Van Nostrand, W.E. (2000) Fibrillar Amyloid ß-Protein Mediates the Pathologic Accumulation of its Precursor in Cerebrovascular Smooth Muscle Cells. J. Biol. Chem. 275:9782-9791.
  
  
• Wagner, M.R., Keane, D.M., Melchor, J.P., Auspaker, K.R., and Van Nostrand. W.E. (2000) Fibrillar Amyloid ß-Protein Binds Protease Nexin-2/Amyloid ß-Protein Precursor: Stimulation of its Inhibition of Coagulation Factor XIa. Biochemistry 39:7420-7427.
  
  
• Van Nostrand, W.E., Melchor, J.P., Keane, D.M., Saporito-Irwin, S.M., Romanov, G. Xu, F. and Davis, J. (2002) Localization of a Fibrillar Amyloid ß-Protein Binding Domain on its Precursor. J. Biol. Chem. 277:36392-36398.
  
  
• Jung, S.S., Zhang, W., and Van Nostrand, W.E. (2003) Pathogenic Aß Induces the Expression and Activation of Matrix Metalloproteinase-2 in Human Cerebrovascular Smooth Muscle Cells. J. Neurochem. 85:1208-1215.
  
  
• Davis, J., Wagner, M.R., Zhang, W., Xu, F., and Van Nostrand, W.E.. Amyloid ß-Protein Stimulates the Expression of Urokinase-type Plasminogen Activator (uPA) and its Receptor (uPAR) in Human Cerebrovascular Smooth Muscle Cells. (2003) J. Biol. Chem. 278:19054-19061.