Synergistic white matter injury from diesel exhaust particulate and chronic cerebral hypoperfusion exposures: Interaction between the Nogo/NgR1 receptor pathway and extravascular fibrinogen toxicity

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Studies suggest an important role for cerebral hypoperfusion and blood brain barrier (BBB) permeability in the onset and progression of cognitive impairment and dementia. Ambient air pollution may differentially impact cognitive health in individuals with underlying cerebrovascular disease. Murine studies demonstrate that particulate matter (PM) exposure and chronic cerebral hypoperfusion (CCH) have supra-additive effects on subcortical white matter injury and neurocognitive deficits. This proposal leverages cell culture studies and a murine bilateral carotid artery stenosis (BCAS) model to assess the effects of Diesel Exhaust Particulate (DEP) in a system that isolates a purely vascular component of cognitive decline and dementia. Potential synergies between axonal growth inhibitors and extravascular fibrinogen deposition are studied as critical regulators of white matter injury and repair. The specific aims of this project are: 1) Examine the role of the Nogo/NgR1 pathway in axonal regeneration and white matter repair following DEP exposure. 2) Establish the roles of BBB permeability and extravascular fibrinogen on axonal regeneration and white matter injury following DEP/CCH exposures and 3) Examine NgR1 and 67KDa Laminin receptor (67 LR) binding/ internalization as a potential therapeutic strategy to mitigate white matter pathology in the setting of DEP/CCH exposures. A factorial design will determine the independent and combined effects of DEP and CCH on white matter toxicity and neurocognition. We expect PM exposure to prime the NgR1 pathway for neurite outgrowth inhibition. We also expect PM exposure to increase plasma fibrinogen levels. Neither of these changes result in substantial white matter injury on their own. We expect CCH to amplify the PM effects on neurite outgrowth inhibition and white matter toxicity. We hypothesize this will occur through 1) decreased cAMP levels secondary to hypoxia that augment DEP-induced axonal growth inhibition and 2) increased BBB permeability that results in extravascular fibrinogen deposition in the subcortical white matter. In addition to causing direct white matter toxicity, fibrinogen can impair axonal regeneration through the integrin b3/ Epidermal Growth Factor Receptor (EGFR) pathway and increased chondroitin sulfate proteoglycan (CSPGs), which can further inhibit white matter repair through the NgR1 pathway. We will assess the impact of epigallocatechin-3-gallate (EGCG) administration to mitigate white matter injury following PM and CCH exposure. We expect this to work through a coordinated strategy of NgR1 and 67LR binding/ internalization and cAMP mediated signaling.