Jin-Moo Lee, MD, PhD
Professor of Neurology
Understanding the molecular pathogenesis of spontaneous intracerebral hemorrhage Read More
|Lab Phone:||(314) 362-7382|
|Lab Location:||BJC Institute of Health 9302|
|Keywords:||Alzheimer's disease, amyloid, stroke, amyloid angiopathy, animal models, 2-photon microscopy, MRI|
Understanding the molecular pathogenesis of spontaneous intracerebral hemorrhage
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.
Hope Center Affiliations
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