Hijacking the Plasminogen Activator System for Possible Therapeutic Potential for Neurovascular and Neurodegenerative Diseases Open Access

Abstract

With the earlier onset of neurovascular and neurodegenerative diseases along with the increasing worldwide life expectancy, the need for therapeutics continues to grow1. In the last two decades, however, the hyperfixation on certain biomarkers and uni-modal treatments continues to abrogate the development of our understanding of these diseases. Aware of this need, this research aims to explore an ischemic stroke system, the Plasminogen Activator System (PAS), and enumerate the contributions to the developments regarding the possible therapeutic potential of this system. Here, the main activators and inhibitors of the PAS are investigated in relation to the astrocytic and neuronal components of the neurovascular unit (NVU). The data presented shows the role of urokinase-plasminogen activator (uPA) in astrocytic wound healing via astrocytic activation, in absence of an injury or pathological state, of the Wingless (WNT) pathway. Additionally, tissue-type plasminogen activator (tPA) is able to contribute not only to astrocytic activation but also to the modulation of cerebral ischemia via the inducement of aquaporin-4 (AQP4) in the astrocytic end feet. Finally, Plasminogen Activator Inhibitor-1 (PAI-1) is shown to increase the morphological complexity of neurons. The demonstrated role of the PAS in astrocytic activation and neuron arborization in this study highlights the future potential of hijacking the PAS in therapeutic target development for neurovascular and neurodegenerative diseases.

Table of Contents

Introduction……………………………………..………………………………………………1-4

Neurovascular Disorders and Neurodegenerative Disease

Plasminogen Activator System

The Neurovascular Unit. Scheme 1: Scheme of the NVU.

Connecting the PAS to the NVU and neurodegenerative diseases: Future of  Synaptogenesis

Materials and Methods………………………………………………….………………………4-8

Astrocytic and Neuronal Primary Culture

Astrocytic Wound Healing Model

Western Blot for Aquaporin 4 (AQP4) Quantification

Immunocytochemistry and Imaging

Sholl Analysis vs. Fractal Analysis

Results…………………………………………………………………………………………8-12

Figure 1: uPA treatment promotes astrocytic wound healing

Figure 2: uPA treatment induces detachment of β-catenin from NCAD-ICD

Figure 3: Preconditioning with tPA increased Aquaporin-4 in neuronal astrocytes

Figure 4: PAI-1 increases neuronal complexity

Discussion…………………………………………………….…………………...………….12-17

Scheme 2: Proposed mechanism of uPA-mediated β-catenin inducement of the WNT pathway for astrocytic wound healing

Scheme 3: Proposed mechanism of astrocytic activation by tPA

Conclusion……………………………………………………….………………………………17

Supplemental Information…………………………….………………...……………………17-18

Supplemental Figure 1

Supplemental Figure 2

References…………………………………………….……………...………………………19-21

About this Honors Thesis

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School	Emory College
Department	Chemistry
Degree	B.S.
Submission	Honors Thesis
Language	English
Research Field	Chemistry, Biochemistry Biology, Neuroscience
Keyword	Neurovascular and Neurodegnerative Diseases
Committee Chair / Thesis Advisor	Smith, Yoland, Emory University
Committee Members	Conticello, Vincent, Emory University Brathwaite, Antonio, Emory University

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