William VanNostrand, PhD

William VanNostrand, PhD
Professor
Department of Neurosurgery
PhD, University of California, Irvine

Phone:(631) 444-1661
Fax: (631) 444-2560
William.VanNostrand@stonybrookmedicine.edu

Department of Neurosurgery
Health Sciences Center T-12
Office: Room 089
Lab: Rooms O86, 090

Education

Research

The research in my laboratory is largely centered on the study of pathogenic mechanisms in neurodegenerative diseases. In our laboratory we take a multi-faceted approach encompassing protein biochemistry, molecular biology, in vitro cell culture models, and in vivo rodent models to understand these pathologic processes. Major efforts include:

1. A major effort is focused on understanding pathogenic mechanisms in cerebral amyloid angiopathy (CAA), a condition that is characterized by accumulation of mis-folded amyloid ß-protein (Aß) in and along brain blood vessels and capillaries. CAA is prevalent in the elderly population and a common comorbididty in Alzheimer’s disease and related disorders. We have generated novel transgenic rodent models that specifically develop CAA in the cerebral microvasculature and showed that this condition promotes a robust localized neuroinflammatory response that leads to behavioral deficits. These models are very useful to study the genesis and consequences vascular amyloid-mediated cognitive impairment and dementia (VCID), an emerging component of dementia in Alzheimer’s disease and related disorders.
2. A common feature of the many neurodegenerative diseases in the accumulation of distinct intra- and extracellular mis-folded proteins, which are specific to the neurodegenerative disease. These proteins assemble into larger structures that then deposit in cells and tissues. For example, AD involves the accumulation of assembled amyloid ß-protein (Aß) as senile plaques and as CAA in blood vessel deposits in brain. There are molecules present in brain the can either promote or inhibit this assembly process. In our lab we have identified novel proteins in brain that can strongly inhibit the assembly and deposition of Aß. We are currently investigating what role these novel “inhibitory” proteins play in preventing pathologic Aß assembly and deposition using relevant transgenic mouse models developed in our lab. Also, we are defining the unique structural features of these “inhibitory” proteins so that we can use the power of them to develop novel therapeutic approaches to suppress pathogenic Aß assembly. We are also expanding the study of these novel “inhibitory” proteins to other neurodegenerative diseases to determine what role they may play and if they are potentially therapeutic for these conditions as well.
3. The Alzheimer’s disease Aß peptide is a small fragment clipped out from a much larger protein known as the Aß protein precursor (AßPP). The function of AßPP remains largely unknown. Through the course of our earlier biochemical work we discovered that AßPP is a strong regulator of enzymes that are involved in the clotting of blood. Since AßPP is abundantly found in brain we hypothesized that it may regulate blood clotting process associated with hemorrhagic and ischemic strokes. Using novel mouse models that were generated in our lab we convincingly showed that indeed AßPP could regulate the severity of stroke. We are presently determining if we can use this protein, and derived fragments as agents for stroke therapy.

Laboratory Personnel

• Judianne Davis – Laboratory Manager and Senior Research Support Specialist
• Michael Hoos – Postdoctoral Researcher
• Feng Xu – Senior Research Associate
• Renee Glasser – Undergraduate Researcher
• Regina Lim – Undergraduate Researcher
• Denise Laspina- Undergraduate Researcher

Representative Publications

• Davis, J., Xu, F., Deane, R., Romanov, G., Previti, M., Zeigler, K., Zlokovic, B.V., and Van Nostrand, W.E. Early-onset and robust cerebral microvascular accumulation of amyloid ß-protein in transgenic mice expressing low levels of a vasculotropic Dutch/Iowa mutant form of amyloid ß-protein precursor. Journal of Biological Chemistry 279:20296-20306 (2004).
• Xu, F., Davis, J., Miao, J., Previti, M.L., Romanov, G., Zeigler, K., and Van Nostrand, W.E. Protease nexin-2/amyloid ß-protein precursor limits cerebral thrombosis. Proceedings of the National Academy of Sciences USA 102:18135-18140 (2005).
• Hoos, M.D., Ahmed, M., Smith, S.O., and Van Nostrand, W.E. Inhibition of familial cerebral amyloid angiopathy mutant amyloid ß-protein fibril assembly by myelin basic protein. Journal of Biological Chemistry 282:9952-9961 (2007).
• Fan, R., Xu, F., Previti, M.L., Davis, J., Grande, A.M., Robinson, J.K., and Van Nostrand, W.E. Minocycline reduces microglial activation and improves behavioral deficits in a transgenic model of cerebral microvascular amyloid. Journal of Neuroscience 27:3057-3063 (2007).
• Xu, F., Previti, M.L., and Van Nostrand, W.E. Increased severity of hemorrhage in transgenic mice expressing cerebral protease nexin-2/amyloid ß-protein precursor. Stroke 38:2598-2601 (2007).
• Ahmed, M., Davis, J., Aucoin, D., Sato, T., Ahuja, S., Aimoto, S., Elliot, J.I., Van Nostrand, W.E., and Smith, S.O. Structural conversion of neurotoxic amyloid-ß(1-42) oligomers to fibrils. Nature Structural & Molecular Biology 17:561-567 (2010).
• Kotarba, A., Aucoin, D., Hoos, M.D., Smith, S.O., and Van Nostrand, W.E. Fine mapping of the amyloid ß-protein binding site on myelin basic protein. Biochemistry 52:2565-2573 (2013).
• Xu, W., Xu, F., Anderson, M.E., Kotarba, A.E., Davis, J., Robinson, J.K., and Van Nostrand, W.E. Cerebral microvascular rather than parenchymal amyloid ß-protein pathology promotes early cognitive impairment in transgenic mice. Journal of Alzheimer’s Disease 38:621-632 (2014).
• Xu, F., Kotarba, A.E., Ou-Yang, M.H., Fu, Z., Davis, J., Smith, S.O., and Van Nostrand, W.E. Early-onset formation of parenchymal plaque amyloid abrogates cerebral microvascular amyloid accumulation in transgenic mice. Journal of Biological Chemistry 289:17895-17908 (2014).
• Ou-Yang, M., Xu, F., Liao, M.-C., Davis, J., Robinson, J.K., and Van Nostrand, W.E. The N-terminal region of myelin basic protein reduces fibrillar amyloid ß-protein deposition in Tg-5xFAD mice. Neurobiology of Aging 36:801-811 (2015).

Patents

• D.D. Cunningham, S.L. Wagner, and W.E. Van Nostrand. Monoclonal Antibodies Specific For Protease Nexin-1 and Purification of Protease Nexin-1 Using Monoclonal Antibodies. United States Patent #5,134,076 (1992).
• W.E. Van Nostrand, S.L. Wagner and D.D. Cunningham. Purification, Detection, and Methods of Use of Protease Nexin-2. United States Patent #5,213,962 (1993).
• W.E. Van Nostrand, S.L. Wagner and D.D. Cunningham. Methods of Diagnosis of Amyloidoses. United States Patent #5,270,165 (1993).
• W.E. Van Nostrand, S.L. Wagner and D.D. Cunningham. Monoclonal Antibody Produced Against Native ß-Amyloid Precursor Protein. United States Patent #5,427,931 (1995).
• W.E. Van Nostrand. Treatment of Amyloidosies Using Myelin Basic Protein and Fragments Thereof. United States Patent #8,815,794 (2014).