The research in my laboratory has largely focused on pathogenic mechanisms in cerebral amyloid angiopathy (CAA) tht is characterized by accumulation of amyloid ß-protein (Aß) in and along brain blood vessels and capillaries. This condition of CAA is prevalent in Alzheimer’s disease and a number of related disorders. We have generated transgenic mice 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 transgenic mice provide a useful model to study vascular amyloid-mediated cognitive impairment, an emerging component of dementia in Alzheimer’s disease and related disorders.
The pathologic accumulation of Aß in brain that occurs in Alzheimer’s disease and related disorders is the largely the result of deficient clearance of the peptide from the central nervous system. In another project in my laboratory we have been characterizing novel enzymes that degrade Aß peptides and novel factors that regulate Aß assembly and deposition in the brain. Both of these processes affect Aß clearance from the central nervous system and play a role in its pathological accumulation.
The Aß peptide is proteolytically derived from a much larger protein known as the amyloid ß-protein precursor (AßPP). Through the course of our studies we have shown that AßPP is potent serine proteinase inhibitor with strong activity towards several key pro-thrombotic enzymes of the coagulation cascade. To this end, we have an active research program studying the activities of AßPP that regulate cerebral thrombosis during stroke and hemorrhage.
- 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).
- Davis, J., Xu, F., Previti, M., Romanov, G., Zeigler, K., and Van Nostrand, W.E. Deficient cerebral clearance of vasculotropic mutant Dutch/Iowa double mutant Aß in human AßPP transgenic mice. Neurobiology of Aging 26:946-954 (2006).
- Colton, C.A., Vitek, M.P., Wink, D.A., Xu, Q., Cantillana, V., Previti, M.L., Van Nostrand, W.E., Weinberg, B., and Dawson, H. NOS2 deletion promotes multiple pathologies in a novel mouse model of AD. Proceedings of the National Academy of Sciences USA 103: 12867-12872 (2006).
- 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).
- Wilcock, D.M., Lewis, M.R., Van Nostrand, W.E., Davis, J., Previti, M.L., Gharkholonareh, N., Vitek, M.P., and Colton, C.A. Progression of amyloid pathology to Alzheimer’s pathology in an APP transgenic mouse model by removal of NOS2. Journal of Neuroscience 28:1537-1545 (2008).
- Xu, F., Vitek, M.P., Colton, C.A., Previti, M.P., Gharkholonarehe, N., Davis, J., and Van Nostrand, W.E. Human apolipoprotein E redistributes fibrillar amyloid deposition in Tg-SwDI mice. Journal of Neuroscience 28:5312-5320 (2008).
- AnneMarie Armenti – Research Support Specialist
- Judianne Davis – Senior Research Support Specialist
- Rong Fan – Postdoctoral Fellow
- Michael Hoos – MCB Graduate Student
- Mei-Chen Liao – MCB Graduate Student
- MaryLou Previti – Research Support Specialist
- Shane McGowan – Undergraduate Student
- Feng Xu – Senior Research Associate