Dr. Lee is the Director of the Cerebrovascular Disease Section and Program Director of the Neurovascular Residency in the Department of Neurology.

Dr. Lee's clinical expertise is in stroke neurology. He attends on the inpatient stroke service, and is an attending physician in the Comprehensive Outpatient Stroke Clinic. He has participated in numerous clinical trials for the treatment and neuroimaging of acute ischemic stroke patients. Dr. Lee is a recipient of the Zaritsky Research Award and the Arthur K. Asbury Resident Award for Clinical Excellence. In addition, he was awarded the Clinical Teacher of Year Award by the Washington University Medical Students, and the Sven Eliasson Award for Teaching Excellence by the Neurology Residents in 2000.

Proteolysis of Amyloid Fibrils in Alzheimer's disease and Cerebral Amyloid Angiopathy

Alzheimer's Disease (AD) is associated with the accumulation of aggregated amyloid-beta peptide (Abeta) in senile plaques within the brain. Abeta1-42, the 42 amino-acid peptide fragment of the amyloid precursor protein (APP), has a striking propensity to aggregate into amyloid fibrils (arranged in a β-pleated sheet conformation) of which compact senile plaques are comprised. This aggregation is thought to be an irreversible process. Despite this strong propensity for self-aggregation, once formed, plaque size remains relatively constant over a wide range of disease durations in AD patients and in AD mouse models. This observation has lead some to believe that compact amyloid plaques exist in dynamic equilibrium, balancing formation with degradation. A growing list of proteases are known to degrade soluble Abeta (sAbeta) in vitro, including neprilysin (NEP), insulin-degrading enzyme (IDE), endothelin-converting enzyme (ECE), angiotensin-converting enzyme (ACE), the plasmin system, and matrix metalloproteinase-9 (MMP-9); however, only recently have a small subset of these proteases been shown capable of degradingfibrillar Abeta (fAbeta). We have recently found that the extracellular matrix-degrading protease, MMP-9, is capable of degrading fAβ in vitro and compact amyloid plaques in situ. Furthermore, we observed MMP-9 immunoreactivity in reactive astrocytes surrounding amyloid plaques, and MMP activity selectively in compact plaques of aged APP/PS1 mice. In addition, conditioned medium from astrocytes contained fAbeta-degrading activity that was inhibited by the MMP inhibitor, GM6001. We are currently pursuing experiments to test the hypothesis that proteases secreted by astrocytes or microglia surrounding compact amyloid plaques limit plaque growth by degrading fAbeta. Furthermore, we propose to examine the molecular mechanisms of amyloid fibril proteolysis.

Cerebral amyloid angiopathy (CAA), the deposition of amyloid in cerebral vessels, is a common finding in the elderly, and especially prominent in patients with AD. In these patients, the Abeta amyloid accumulates in cerebral vessels leading to vascular degeneration, and can result in fatal hemorrhagic strokes. The molecular pathogenesis of CAA-related hemorrhage is poorly understood. In addition to its expression around amyloid plaques, we have found that MMP-9 is also upregulated surrounding amyloid-laden vessels. While the protease may play a role in degrading amyloid, another potential consequence is the breakdown of the extracellular matrix and vascular basement membrane of the arterioles affected in CAA. We are currently testing the hypothesis that Abeta amyloid, which accumulates in cerebral blood vessels in CAA, induces vascular MMP-9 activity leading to breakdown of the vascular basement membrane, contributing to the development of spontaneous hemorrhagic stroke.

Alternative pre-mRNA Splicing Regulates Vulnerability to Cerebral Ischemia

Greater than 70% of human genes employ alternative pre-mRNA splicing as a means of regulating expression. In some cases, alternative splicing may result in mRNA isoforms coding for proteins with opposing activities, suggesting a critical role in the regulation of a variety of physiologic processes. Preliminary evidence suggests that pre-mRNA alternative splicing may play a role in the regulation of apoptosis and cell death. For example, the apoptosis regulator gene, bcl-x, generates two mRNA isoforms with opposing actions: Bcl-xL (the longer transcript) is anti-apoptotic, while Bcl-xS is pro-apoptotic. We have recently found that hypoxia-ischemia (H-I) in neonatal rats (a model of ischemia with prominent apoptosis) resulted in a significant decrease in the Bcl-xL/Bcl-xS mRNA ratio in the ischemic hippocampus and cortex, while the contralateral side remained unchanged compared to controls. Because oligodendrocyte progenitors (OPs) are particularly vulnerable to H-I at this age, we investigated Bcl-x splicing in OPs induced to undergo apoptosis with C2-ceramide. Within 1 hours of exposure, the Bcl-xL/Bcl-xS mRNA ratio was decreased (well before caspase-3 activation and cell death). We are currently testing thehypothesis that alternative splicing of Bcl-x may be an early and important regulator of apoptosis and cell death in neonatal hypoxia-ischemia. If this hypothesis is correct, specific regulators of RNA splicing may be identified as novel therapeutic targets for neonatal H-I. Furthermore, results from our proposed studies may provide insights into a novel injury mechanism in other neurological diseases as well.

Medical Training

Dr. Lee graduated from Yale College in 1985, majoring in Molecular Biophysics and Biochemistry. He subsequently enrolled at Cornell University Medical College where he obtained both a Ph.D. and M.D. degree in 1992 and 1993. His dissertation focused on the role of a novel neurotrophic factor in the differentiation of neurotransmitter traits in developing sympathetic neurons, under the mentorship of Dr. Ira Black. After training as an intern and resident in neurology at the Hospital of the University of Pennsylvania, he completed a cerebrovascular fellowship at Washington University School of Medicine. He then received post-doctoral training under the co-mentorship of Drs. Dennis Choi and Chung Y. Hsu. He is currently an Assistant Professor of Neurology.

Selected Publications

Yin KJ, Cirrito J, Yan P, Hu X, Xiao Q, Pan X, Bateman R, Song H, Hsu FF, Turk J, Xu J, Hsu CY, Mills J, Holtzman DM, Lee J-M. Matrix metalloproteinases expressed by astrocytes mediate extracellular Abeta catabolism. J Neurosci 2006 26:10939-10948.

Yan P, Hu X, Song H, Yin K, Bateman RJ, Cirrito JR, Xiao Q, Hsu FF, Turk JW, Xu J, Hsu CY, Holtzman DM, Lee J-M. Matrix metalloproteinase-9 degrades amyloid-beta fibrils in vitro and compact plaques in situ. J Biol Chem 2006 281:24566-24574.

Yin KJ, Hsu CY, Hu XY, Chen H, Chen S, Xu J, Lee J-M. PP2A regulates bim expression via the Akt/FKHRL1 signaling pathway in Abeta-induced cerebrovascular endothelial cell death, J Neurosci 2006 26:2290-2299.

Lee J.-M., Yin K.J., Hsin I., Chen S.W., Fryer J.D., Holtzman D., Hsu C. Y., Xu J, Matrix Metalloproteinase-9 and Spontaneous Hemorrhage in an Animal Model of Cerebral Amyloid Angiopathy. Ann Neurol. 54:379-382, 2003.

Vo K.D., Santiago F., Lin W., Hsu C.Y., Lee Y.Z., Lee J.-M., Enhancement patterns in magnetic resonance imaging as predictors of hemorrhagic transformation in acute ischemic stroke. Am J Neurorad, 24(4):674-9, 2003.

Lee J.-M., Vo K.D., An H., Celik A., Lee Y., Hsu C.Y., Lin W., MR cerebral metabolic rate of oxygen utilization in hyperacute stroke patients. Ann Neurol. 53:227-232, 2003.

Lin W., Lee J.-M., Lee Y.Z., Vo K.D., Pilgram T, Hsu C.Y., Temporal relationship between apparent diffusion coefficient and absolute measurements of cerebral blood flow in acute stroke patients. Stroke, 34(1):64-70. 2003.

Yin K.J., Lee J.-M., Chen S.D., Xu J. and Hsu C.Y. Amyloid Beta induces smac release via AP-1/ Bim activation in cerebral endothelial cells. J Neurosci, 22(22):9764-70, 2002.

Lee J-M. and Choi D.W. Neuroprotection in cerebral ischemia. In Diseases of the Nervous System. Ed: Asbury A.K., McKhann G.M., McDonald W.I., Goadsby P.J., and McArthur J.C. Cambridge University Press. Cambridge, UK, pp 62-78, 2002.

Lee, J-M., Zipfel, G.J., Park, K.H., He, Y.H., Hsu, C.Y., and Choi, D.W. Zinc translocation accelerates the development of infarction after mild transient focal ischemia. Neurosci, 115(3):871-8, 2002.

Lee J.-M., Grabb M.C., Zipfel G.J., Choi D.W. Brain tissue response to ischemia, J Clinical Investigation, 106(6):723-731, 2000.

Zipfel G.J., Lee J.-M., Choi D.W. Reducing calcium overload in the ischemic brain, New England Journal of Medicine, 341(20):1543-1544, 1999.

Lee J.-M., Zipfel G.J., Choi D.W. The changing landscape of ischaemic brain injury, Nature, 399:A7-A14, 1999.