Date of Award

12-31-2019

Document Type

Dissertation

Degree Name

Doctor of Philosophy in Biomedical Engineering - (Ph.D.)

Department

Biomedical Engineering

First Advisor

Haorah, James

Second Advisor

Chandra, N.

Third Advisor

Belfield, Kevin D.

Fourth Advisor

Ye, Jiang-Hong

Fifth Advisor

Pang, Kevin

Abstract

Efficient clearance of interstitial waste metabolites is essential for normal brain homeostasis. Such effective clearance is hampered by the lack of a lymphatic system in the brain, and the cerebrospinal fluid (CSF) is unable to clear large size waste metabolites in the brain. Here, a novel idea that brain arterial endothelium and smooth muscle cells reactivity regulates the clearance of these water-insoluble large size waste metabolites through the perivascular dynamic exchange, and that low dose ethanol promotes this perivascular clearance is proposed.

In Aim 1, the biodistribution of a large size waste metabolite (Amyloid-β protein mimic) in rat perivascular space as a proof-of-concept is examined. Then the effects of low dose alcohol (ethanol) for promoting perivascular clearance path are evaluated. The result shows that ethanol increases perivascular clearance by enhancing the dilative reactivity of arterial endothelial cells (ECs) and alpha-smooth muscle cells (α-SMCs) via the activation of endothelial specific nitric oxide synthase (eNOS) and nitric oxide (NO) production. In Aim 2, the underlying molecular mechanisms of low dose ethanol on the perivascular clearance of waste metabolites is examined. The result shows that low dose ethanol specifically activates eNOS in arterial wall and generates physiological favorable level of NO without affecting the integrity of the Blood-Brain Barrier (BBB). This vasodilator NO stimulates the dilative reactivity of ECs- α-SMCs, which promotes

the diffusive movement of waste metabolites from interstitial space/CSF to perivascular-perivenous drainage path. Decrease in phosphorylation of myosin light chain in α-SMCs and increase in arterial vessel diameter validates α-SMCs reactivity and movement of waste metabolites towards perivascular space. In Aim 3, the contrast effects of chronic moderate alcohol intake on perivascular clearance of waste metabolites is assessed. The result reveals that chronic alcohol intake switches the induction of eNOS to inducible nitric oxide synthase (iNOS), thereby generating high level of NO. This continuous production of NO by iNOS in chronic alcohol exposure causes oxidative damage of the arterial endothelial-smooth muscle layers, and reduces dilative reactivity. Decrease in tight junction protein levels validates the BBB dysfunction, and increase in phosphorylation of myosin light chain in α-SMCs validates the impairment of α-SMCs reactivity, that are closely correlated with decrease in waste metabolites movement towards perivascular clearance path.

The current work affords huge clinical relevance since aggregation of large size waste metabolites like Ab protein around the perivascular space is a hallmark of Alzheimer's disease. As such, the findings suggest new strategies for prevention and treatment of neurological diseases that are associated with clearance of entangled proteins.

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