Remyelination failure is the hallmark of microvascular white matter injury (WMI) and commonly causes cognitive impairment and dementia in the elderly. We propose that remyelination failure involves two complementary mechanisms that generate hyaluronic acid fragments (HAf) that disrupt the maturation of oligodendrocyte progenitor cells (OPCs). First, we hypothesize that vascular endothelial cells generate HAf in response to oxidative stress. Second, we hypothesize that vascular injury activates HAf-mediated mechanisms that promote vascular lumen adhesion and trafficking of lymphocytes to cause white matter inflammation and reactive astrocytosis to enhance HA/HAf levels. We will focus on human WMI confirmed by ante-mortem MRI- defined white matter hyperintensities (WMHs). WMHs are the most widely used clinical predictor of risk for vascular cognitive impairment and dementia (VCID). We will define aberrant HAf-mediated actions related to cerebrovascular dysfunction in WMHs. We will build upon two recent advances. First, we will undertake novel vascular physiology studies to define oxidative stress in arterioles isolated from human WMHs. We showed that WM arterioles from VCID cases selectively displayed reduced endothelium-mediated vasodilation that predisposes to WMI (Ann Neurol 83:142-152, 2018). Second, we will define aberrant HAf- mediated mechanisms of myelination failure related to cerebrovascular dysfunction in WMHs. We have defined a signaling pathway activated by cerebral ischemia where a specific bioactive HAf cell autonomously blocks OPC maturation to cause myelination failure (J Clin Invest 128:2025-2041, 2018). We will thus utilize our unique expertise in quantitation and analysis of HA fragments to determine the specific sizes that are linked to myelination failure in WMHs through mechanisms involving the OPC-vascular niche.
In aim 1, we will employ a combination of molecular and morphometric approaches to test the hypothesis that remyelination failure in WMHs arises from disrupted HA metabolism that mediates aberrant OPC proliferation and blocks differentiation to myelinating oligodendrocytes. We will isolate vascular endothelial cell-derived HAf from WMHs and determine its actions on OPC proliferation and differentiation.
In aim 2, we will utilize a combination of molecular, biochemical and histochemical approaches to test the hypothesis that WM vascular dysfunction and oxidative/nitrosative stress are linked to altered HA synthesis, catabolism and signaling in WMHs.
In aim 3, we will employ novel murine and human in vitro models to test the hypothesis that dysfunction of WM arterioles promotes inflammatory mechanisms of myelination failure mediated by vascular lumen adhesion and trafficking of lymphocytes into WMHs. Our over-riding objective is to provide a mechanistic molecular explanation for the distinct OPC-vascular processes that render aging human white matter particularly susceptible to microvascular WMI in order to develop therapies that promote OPC maturation and mitigate remyelination failure associated with cognitive decline in VCID.

Public Health Relevance

This proposal focuses on recently discovered mechanisms of impaired regeneration and repair of diffuse human white matter lesions that we propose are central to vascular brain injury and cognitive decline associated with aging and vascular dementia. We will employ pioneering vascular physiology and molecular approaches to define how chronic injury and inflammation of human white matter blood vessels contributes to the progression of white matter injury by studying MRI-defined lesions from human autopsy brains from patients confirmed to have cognitive decline. The role of disrupted white matter blood flow will be related to disrupted maturation of a key brain cell type (the oligodendrocyte progenitor) that appears to play a central role in aberrant brain recovery (remyelination failure) after white matter injury to be defined by MRI.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Multi-Year Funded Research Project Grant (RF1)
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Brain Injury and Neurovascular Pathologies Study Section (BINP)
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Mackiewicz, Miroslaw
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Oregon Health and Science University
Schools of Medicine
United States
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