Thursday March 30th 2017, 4:00pm
Ischemic stroke is a worldwide leading cause of death and morbidity with few therapeutic options. One focus of research in my lab is the development of novel neuroprotective and neuroreparative stroke therapies derived from the brain’s response to ischemic injury. We have determined that a small protein fragment of the extracellular matrix heparan sulfate proteoglycan perlecan, termed domain V (DV), is acutely and persistently elevated in the brain after experimental and human stroke. Prevention of this increase in mouse transient middle cerebral artery occlusion (MCAo) results in larger infarcts, diminished angiogenic neurorepair and worse functional outcomes suggesting that this post-stroke DV generation is of consequence. Mice treated acutely (within 24 hours) or in a delayed (7 days) fashion with human recombinant DV have smaller brain infarcts, enhanced angiogenesis, enhanced neurogenesis and significantly improved functional outcomes. Additionally, astrocytic responses appear to be acutely enhanced and chronically suppressed. Further analysis identified a specific endothelial cell receptor, alpha5beta1 integrin, to be responsible for most of DV’s therapeutic benefits. Importantly, this receptor, while expressed during brain development by endothelial cells, is downregulated in the adult human brain but upregulated after stroke in infarct and peri-infarct vasculature, a context dependent expression that makes it a particularly attractive therapeutic target. Intriguingly, mice with endothelial cell selective knockdown of alpha5beta1 integrin are profoundly resistant to ischemic stroke, potentially via enhanced stability of their blood-brain barrier after MCAo. Furthermore, new results suggest that pharmacologic blockade of the alpha5beta1 integrin after experimental stroke in wild type mice and rats (collaboration with Dr. Christopher McCabe, University of Glasgow) may also be significantly beneficial.
Alzheimer’s disease (AD) and vascular dementia (VaD) are the first and second leading causes of dementia, respectively. AD is believed to be caused by a combination of the extracellular accumulation of oligomeric amyloid beta (Aβ) and the intracellular accumulation of Tau neurofibrillary tangles. Despite this, VaD in particular remains woefully understudied and poorly understood, in part due to its diverse etiology. One way in which the brain may attempt but ultimately fail to compensate for the vascular injury and resultant hypoperfusion (often the result of perivascular accumulation of Aβ) that underlies VaD is via angiogenesis, a complex process of new blood vessel growth that is regulated by growth factors, homo- and heterotypic cell interactions, and the extracellular matrix. Importantly, in two experimental animal models of VaD, the bilateral carotid artery stenosis mouse model (BCAS) and the diabetic APP/PS1 knock in mice (db/AD, a leptin resistance diabetic mouse that also overexpresses human Aβ in its brain), brain angiogenesis and DV levels are both increased early on, only to be diminished as pathology and dementia worsens. Importantly, we have determined that DV is capable of blocking Aβ neuro- and angiotoxicity, and greatly enhances Aβ brain clearance via augmenting the activity of the endothelial transporter P-glycoprotein. Therefore, we hypothesize that DV plays a key role in the brains endogenous response (compensatory angiogenesis and Aβ clearance) to cerebrovascular insult that can be therapeutically exploited.
Professor Gregory Bix
Associate Professor of Neurology
from the University of Kentucky
Centre for Stroke & Brain Imaging